WO1996000733A1 - Diphosphate or triphosphate non-hydrolysable stable analogues and methods for their preparation - Google Patents

Abstract

Diphosphate or triphosphate non-hydrolysable stable analogues and methods for their preparation. These analogues are of formula (I) in which R<1>, R<2>, R<3>, R<4> and R<5> are a hydrocarbon group, an aryl group, a quaternary ammonium group or a metal ion, R<5> can also be a nucleoside derivative, X<1> and X<2> are CH2, CHF, CF2, CC12, CHC1 or NR<6> and n=0 or 1. The analogues of the invention are for pharmaceutical, biological and therapeutical use.

Description

Stable, non-hydrolyzable analogues of diphosphates or triphosphates and methods of their preparation

 The present invention relates to stable, non-hydrolyzable analogs of diphosphates and triphosphates, which can be used in particular as intermediates for the preparation of biologically active molecules or as biologically active molecules.

 Many biologically active molecules have di and triphosphates units whose chemical stability is low given the ease with which the pyrophosphate chain is hydrolyzed. Also, stable analogues of these molecules would be of great interest in various fields such as pharmacy, biology and therapeutic monitoring.

 In fact, living cells capture, store and transport energy in chemical form, essentially in the form of adenosine triphosphate (ATP). ATP can transmit its energy to certain other molecules and thus release its terminal phosphate group; the energy-rich ATP molecule then becomes adenosine diphosphate (ADP) whose energy has decreased, but which can regain a phosphate group to become ATP again thanks to a supply of solar energy in photosynthetic cells , or chemical energy in animal cells.

ATP is the main connecting link between two major sets of enzyme-catalyzed reactions in cells. One of these sets conserves chemical energy from the environment by causing phosphorylation of energy-poor ADP, energy-rich ATP. The other set uses the energy of ATP to perform the biosynthesis of cellular components from simple precursors, to do mechanical work necessary for contraction and locomotion, or to perform osmotic work of membrane transport. These sets of enzyme catalyzed reactions are almost identical in all living species.

 Also, ATP or ADP can be used in many techniques, for example to immobilize, orient or transport molecules of biological interest.

 However, these techniques are limited due to the low chemical stability of ATP and ADP. It would therefore be of great interest to have analogs of ATP or ADP, which are not hydrolysable to fulfill these functions.

 The present invention specifically relates to stable analogues of diphosphates and triphosphates, capable of being coupled to biological molecules for various applications in fields such as pharmacy, medicine, monitoring therapeutic treatments, etc.

 According to the invention, the stable, non-hydrolyzable analog of diphosphate or triphosphate corresponds to the formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ which may be the same or different, represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group having one or more ethylenic bonds, an aralkyl group, an aryl group, a benzyl group unsubstituted or substituted by an alkyl group, a group derived from nucleoside or a group derived from a biomolecule;

- R ⁵ represents a hydrogen atom, an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valency state of metal M, a derivative group, of a nucleoside or a group derived from a biomolecule; - X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCI ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group; - X ³ represents O, S, or NH;

- n is equal to 0 or 1; and

- when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from the groups alkyl and / or aryl, or include an optionally substituted phenyl ring, provided that at least one of R ¹ and R ⁵ is a benzyl group and that X ¹ does not represent CH ₂ , CHF, CF ₂ , CCI ₂ or CHCl when n = 0 and R ⁵ represents something other than a group derived from nucleoside or from a biomolecule. In these analogs, the POP bonds of diphophates and triphosphates are replaced by bonds of the P-CH ₂ -P, PN (R ⁶ ) -P, P-CF ₂ -P, P-CCl ₂ -P, P-CHCl type. -P or P-CHF-P which are much more stable and non-hydrolyzable, and can preserve the ability of the triphosphate or diphosphate to combine with biological molecules or with other compounds for the desired applications.

In the formula I given above, the alkyl groups capable of being used for R ¹ ,

R ² , R ³ , R ⁴ , R ⁵ and R ⁶ can be linear or branched groups having from 1 to 10 carbon atoms, for example methyl, ethyl groups.

The hydrocarbon groups comprising one or more ethylenic bonds capable of being used in formula (I), may be linear or branched and preferably contain 2 to 10 carbon atoms.

As an example of such a group, mention may be made of the allyl group.

In the case where aralkyl or aryl groups are used for R ¹ , R ² , R ³ , R ⁴ , R ⁵ and / or R ⁶ , the aryl part can be derived from aromatic hydrocarbons such as benzene, naphthalene, anthracene, etc. In the case of aralkyl groups, the alkyl part generally has from 1 to 3 carbon atoms. As examples of aryl and aralkyl groups of this type, mention may be made of phenyl and benzyl groups and groups of formula

in which n = 1 or 2 and R is an alkyl group, the 2 Rs being able to be different when n = 2.

 When a benzyl group is used, it can be substituted on its alkyl or phenyl part by an alkyl group, preferably comprising 1 to 6 carbon atoms.

The quaternary ammonium groups which can be used in the invention can be derived from an optionally cyclic tertiary amine or correspond to the formula NR ₄ with R representing an alkyl or aryl group, the R being able to be different and two R being able to form together a saturated ring or aromatic.

By way of example of quaternary ammonium groups which can be used, mention may be made of groups derived from 1,4-diazabicyclo [2,2,2] octane and quinuclidine. It can also be the NH ₄ ^{+ group} .

In the metal of formula M _{1 / v '} M can represent different metals, in particular an alkali metal such as Na or K.

In the case of a group derived from a nucleoside, it may be a nucleoside formed from ribose or deoxyribose, with the various pyrimidine or purine bases. Generally, this nucleoside-derived group is joined to the phosphate group via the primary alcohol function of ribose or deoxyribose. Furthermore, these nucleoside-derived groups may contain substituents, in particular on purine or pyrimidine bases, to give them, for example, pharmaceutical properties.

R ¹ and / or R ⁵ can also represent a group derived from a biomolecule. Biomolecule means any molecule with biological activity. Examples of such molecules include:

 - lipids (phospholipids, fatty acids, prostaglandins, prostacyclins, leukotrienes, steroids ...) and derivatives,

 polysaccharides and derivatives (inositols, aminosugars ...),

 - hormones and derivatives,

 - drugs and substances with therapeutic activity, natural or synthetic,

 - amino acids and peptides,

 - vitamins, and

 - probes (radiolabelled, fluorescent, photoactivable, etc.).

 According to a first embodiment of the invention, the analogs are triphosphate analogs, and in this case n = 1.

In this first embodiment of the invention, very interesting analogs are those in which X ³ represents 0 and R ¹ , R ² , R ³ , R ⁴ and R ⁵ all represent the same hydrocarbon group, for example an aralkyl group , such as the benzyl group. Such analogs are useful as intermediates, for subsequent reactions such as coupling with various derivatives of nucleosides or biomolecules.

When in these analogs, X ¹ and X ² represent N (R ⁶ ), the two R ⁶ preferably form a hydrocarbon chain of 2 to 7 carbon atoms which includes a phenyl ring.

By way of example of hydrocarbon chains of this type, mention may be made of those of formula - (CH ₂ ) ₂ - or

 According to a second embodiment of the invention, the analogs are analogs of diphosphates, and, in this case, n = 0.

In this case, X ¹ is advantageously NH or N-benzyl, R ¹ , R ² , and R ⁴ are allyl or benzyl groups and R ⁵ is the benzyl group.

When X ¹ is CF ₂ , R ¹ and R ² are advantageously ethyl groups, R ⁴ is the methyl group and R ⁵ is the benzyl group or a hydrogen atom.

 Other interesting analogs are those of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ which may be identical or different, represent a hydrogen atom, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal, an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group having one or more ethylenic bonds, an aralkyl group, an aryl group or an unsubstituted or substituted benzyl group by an alkyl group, a group derived from nucleoside or a group derived from a biomolecule;

- R ⁵ represents a hydrogen atom, an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valency state of metal M, a derivative group, of a nucleoside or a group derived from a biomolecule;

- X ¹ and X ² which may be identical or different, represent NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- X ³ represents O, S, or NH; and

- n is equal to 1; provided that at least one of R ¹ , R ² , R ³ and R ⁴ is a hydrogen atom, an ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal, and that at least one of R ¹ , R ² , R ³ and R ⁴ is different from a hydrogen atom, a quaternary ammonium group, and a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal.

The subject of the invention is also methods of preparing diphosphate and triphosphate analogues of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ which may be the same or different, represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylene bonds, an aralkyl group , an aryl group, a group derived from nucleoside or a group derived from a biomolecule; - R ⁵ represents an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group except the benzyl group, or benzyl substituted by an alkyl group, an aryl group, a group derived from a nucleoside or a group derived from d 'a biomolecule;

- X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCI ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- n is equal to 0 or 1 and - when n is equal to 1 with X ¹ and X ² representing both NR ⁶ , the two R ⁶ can together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which can have one or more substituents chosen from alkyl and / or aryl groups, or include an optionally substituted phenyl ring. According to a first embodiment of this method, it comprises the following steps:

 a) prepare a compound of formula:

in which R ' ¹ , R' ² , R ' ³ and R' ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylene bonds, an aralkyl group or an aryl group, X ¹ , X ² and n are as defined above, and Bn is a benzyl or benzyl group substituted by an alkyl group, R ' ² and R' ⁴ being identical when R ' ¹ is a benzyl group or benzyl substituted with an alkyl group,

b) subjecting the compound obtained in a) to a monodeprotection to replace the group Bn with H, M _{1 / v} with M being a metal and v being the valence of this metal, or a quaternary ammonium group,

c) reacting the compound obtained in b) with an alcohol of formula R ⁵ OH in which R ⁵ has the meaning given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

According to a second embodiment of this process, it comprises the following steps: a) preparing a compound of formula:

in which :

- R ' ¹ , R' ² , R ' ³ and R' ⁴ , independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group or an aryl group, X ¹ , X ² and n are as defined above, and Me is a methyl group, R ' ² and R' ⁴ being identical when R ' ¹ is a methyl group,

 b) subjecting the compound obtained in a) to a mono-protection to replace the group Me by H,

M _{1 / v} with M representing a metal and v being the valence of this metal,

c) reacting the compound obtained in b) with an alcohol of formula R ⁵ OH in which R5 has the meaning given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

One can also prepare analogs of diphosphate or triphosphate of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a group derived from nucleoside or a group derived from a biomolecule. - R ⁵ represents an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group except the benzyl group or benzyl substituted by an alkyl group, an aryl group, or a group derived from a nucleoside or a group derived from d 'a biomolecule;

- X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- X ³ represents S or NH,

- n is equal to 0 or 1. by analogous methods starting from the starting compounds used above, comprising a benzyl, substituted benzyl or methyl group, then carrying out the following steps: b) subjecting the compound obtained in a) to a mono-protection to replace the group Bn (or Me) by H, M _{1 / v} with M being a metal and v being the valence of this metal, or a quaternary ammonium group,

c) reacting the compound obtained in b) with a compound of formula R ⁵ X ³ H to replace OH by X ³ R ⁵ , X ³ and R ⁵ having the meanings given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

 The methods described above are very advantageous because they make it easy to produce analogs of diphosphates or triphosphates comprising the desired groups at the desired locations.

 Indeed, the processes comprise three essential stages which are:

 a) the preparation of an analog whose all the acid functions are protected.

 b) regioselective monodeprotection of one of these functions which is protected by a methyl or benzyl group, and

 c) the reaction of the deprotected acid function with a reagent suitable for the introduction of a new group, in particular a biomolecule or a nucleoside.

Thus, starting from a starting product which contains a benzyl or methyl group, it is easy to obtain a regioselective and quantitative monodeprotection, which then makes it possible to carry out on the monoacid or the corresponding salt obtained in b) the reactions necessary for introduce the desired group to the desired place, while all the other phosphoric esters of the analog are preserved.

This point constitutes an important innovation and the possibility of preparing analogs of polyphosphates in the form of monoacids or of corresponding salts allows transformations which are not possible, or much more difficult, with the same molecule in its fully hydrolyzed form (R ¹ to R ⁵ = H). In addition, the esterification of these monoacids or of the corresponding salts can be carried out directly with an alcohol R ⁵ OH, via a Mitsunobu reaction (or any other suitable method) without it being necessary to carry out a prior activation of the 'alcohol.

 These possibilities of regioselective and successive monodeprotections, followed by functionalizations are very advantageous for obtaining various compounds which are very difficult or impossible to obtain until now.

 According to the invention, it is also possible to prepare a diphosphate or triphosphate analog of formula:

in which R ² , R ³ and R ⁴ represent H, a metal of formula M _{1 / v} with M being the metal and v the valence of this metal, or a quaternary ammonium group, R ¹ is identical to R ² , R ³ and R ⁴ or is a group derived from nucleoside or a biomolecule, X ¹ , X ² and n have the meanings given in claim 1, and R ⁵ represents a group derived from nucleoside or a biomolecule, by reacting a compound of formula:

in which R ¹ represents H or has the meaning given in claim 1, R ² , R ³ , R ⁴ , X ¹ , X ² and n have the meanings given in claim 1 with a compound of formula R ' ⁵ OH in which R ' ⁵ is the group R ⁵ or a precursor thereof, and then eliminating the groups R ² , R ³ , R ⁴ and optionally R ¹ to replace them with H, M _{1 / v} or a quaternary ammonium group .

 For this complete elimination of groups

R ¹ , R ² , R ³ and R ⁴ , complete deprotection is carried out, for example hydrolysis in basic medium or catalytic hydrogenation when the groups to be eliminated are benzyl groups.

 In the case of the selective monodeprotection of step b) of the methods described above, that is to say when it is desired to carry out the deprotection of a single group, with a high yield, various techniques can be used. depending on the nature of the group to be replaced.

Thus, in the case where this group is an aralkyl group such as the benzyl group or a substituted benzyl group, this monodeprotection can be accomplished using a stoichiometric amount of tertiary amine, preferably DABCO (1,4-diazabicyclo [2 , 2,2] octane) or quinuclidine, in toluene at reflux for a few hours. The quaternary ammonium salt obtained can then be the object of a protonation or of a cation exchange using a resin. When the group to be replaced is an alkyl group such as the methyl group, this monodeprotection can be accomplished by using potassium cyanide in dimethylformamide DMF at 70 ° C for a few hours. The salt obtained can also be the subject of an ion exchange as described above.

In the case of a selective deprotection relating to the group R ′ ³ of the central phosphorus atom, a selective monodeprotection can be carried out under the same conditions as above provided that R ′ ³ is different from R ′ ¹ , R ′ ² , R ' ⁴ and R' ⁵ , for example R ' ³ being a benzyl or methyl group.

The starting materials used in the methods of the invention which contain a benzyl, substituted benzyl or methyl group can be easily prepared by the Michaelis Arbuzov reaction when X ¹ and X ² both represent CH ₂ .

When R ¹ and R ² are identical, the compound of formula is prepared:

by reaction of a bis- (halomethylene) phosphinate of formula:

in which R ³ is as defined in claim 1 and X is a halogen atom, with two equivalents of a benzyl phosphite of formula:

wherein Bn is benzyl or substituted benzyl and R ' ² is as defined in claim 19.

 In the case where one wants to introduce a group Me instead of Bn, this compound is prepared by carrying out the following successive steps:

 a) reacting a bis- (halomethylene) phosphinate of formula:

wherein R ' ³ is as defined in claim 1 with an equivalent of a benzyl phosphite of the formula: R

in which R ' ¹ and R' ² are as defined in claims 20 and 21, and Bn is a benzyl or substituted benzyl group to obtain a compound of formula:

and

b) reacting the compound thus obtained with an equivalent of a benzyl phosphite of formula:

wherein R ' ⁴ is as defined in claims 20 and 21, Bn is a benzyl or substituted benzyl group and Me is a methyl group.

When n is equal to 0 and X ¹ represents CH ₂ , it is also possible to use the reaction of Michalis Arbuzov to prepare the starting product of formula:

by reaction of a halomethylenephosphonate of formula:

in which R ' ¹ and R' ² are as defined in claim 18 and X is a halogen atom, with a benzyl phosphite of formula:

wherein Bn is benzyl or substituted benzyl and R ' ⁴ is as defined in claim 18.

In the case where Bn is replaced by Me in the starting product, a benzyl phosphite of formula:

 The use of Michaelis reaction

Arbuzov for preparing the starting materials used in the processes of the invention, also constitutes an important innovation for obtaining analogues protected by various groups. With such analogues, it is then possible to carry out several successive functionalizations by renewing the steps of monodeprotections and of reaction of the deprotected function.

 The starting materials used for these Michaelis Arbuzov reactions can be prepared by conventional methods.

 Thus, bis- (halomethylene) phosphinate can be prepared according to the methods described by Ivanov et al in Zh. Obshch. Khim., 1967 37 (8), p. 1856-1862, and by Frank et al in Can. J. Chem., 1966, 44, p. 2593-2596.

Mixed phosphite can be prepared by successive reactions of different alcohols R ' ¹ OH, R' ² OH, and benzyl alcohol BnOH, in the presence of a base, on PCI ₃ . Generally, the Arbuzov reaction is carried out at a temperature of 140 ° C., under low pressure, for example under 4 mm of mercury. Preferably, the reaction medium is further subjected to violent stirring to continuously remove the benzyl halide formed.

When n = 1 and X ¹ = X ² = CH ₂ , the starting product obtained by this reaction necessarily has the same hydrocarbon-based alkyl groups comprising one or more ethylenic, aralkyl or aryl bonds in the positions R ' ² and R' ⁴ of formula (I).

Also, when one wants to obtain a starting product in which R ⁴ and R ⁵ are different, the synthesis is carried out in 2 stages following 2 Arbuzov reactions successively with 2 suitable phosphites:

To prepare the formula starting material

in which the two R ⁶ form a hydrocarbon chain R9 as defined above, the following steps can be carried out: a) reacting two chlorophosphates of formulas:

with a diamine of formula:

H ₂ NR ⁹ -NH ₂ in which R ' ¹ , R' ² , and R ' ⁴ are as defined in claim 18, and R ⁹ has the meaning given above to form a bis-phophoramide,

 b) cyclizing the bis phosphoramide thus obtained on a dichlorophosphite of formula:

CI ₂ P-OR ' ³ in which R' ³ is as defined in claim 18, and

c) oxidizing the cyclized product thus obtained. The starting material with Me instead of Bn can be prepared in the same way using in the first step:

 When two different chlorophosphates are used for this preparation, these are reacted successively with the diamine.

Furthermore, it is possible in this process to carry out the steps of monodeprotection of R ' ¹ , R' ² , R ' ⁴ and R' ⁵ and their replacement by the desired R ¹ , R ² , R ⁴ and R ⁵ , before the steps b) and c) cyclization and oxidation.

 The diamine used as the starting material in this reaction can be synthesized by conventional methods such as those described by Carpino in J. Org. Chem., 1986, 51, p. 4768-4779.

 In this process, the first reaction corresponds to a diphosphorylation of the diamine and this reaction can be carried out in the presence of two equivalents of triethylamine. This reaction is very rapid and allows the diphosphoramide to be obtained with a high yield. The diphosphoramide is then cyclized with a dichlorophosphite in the presence of triethylamine and 4-dimethylaminopyridine, in an appropriate organic solvent such as tetrahydrofuran.

The oxidation of the cyclized product can then be carried out with 4-chloroperbenzoic acid. After this reaction, a triphosphate analog of formula (I) is obtained in which X ₁ and X ₂ are groups NR ⁶ and R ¹ , R ² , R ³ R ⁴ and R ⁵ are alkyl or benzyl groups. A monodeprotection of this analog can be carried out selectively on one of the two hexocyclic phosphoramides or on that included in the cycle provided that the group of phosphoramide included in the cycle is different from the other two. As we have seen before, in the case where the groups to be replaced by a hydrogen atom are benzyl groups, monodeprotection can be carried out using a tertiary amine.

 When these groups are methyl groups, selective monodeprotection can be carried out using potassium cyanide in dimethylformamide as described above.

 When we want to carry out a selective deprotection of the phosphorus included in the cycle, we use the same deprotection modes.

 In all cases, the group located on the phosphorus of the cycle must be different from the groups located on the exocyclic phosphors.

 It is also possible to carry out total deprotection by catalytic hydrogenation as seen previously.

To prepare a triphosphate analog in which X ¹ and X ² are respectively the groups CH ₂ and NR ⁶ , one can use for the preparation of the compound of formula:

a process which consists in reacting a methyl phosphonate of formula:

with a diphosphate analog of the formula:

O

in which R ' ¹ , R' ² , R ' ³ , and R' ⁴ are independently alkyl, aryl or aralkyl groups, or hydrocarbon groups having one or more ethylenic bonds.

 The diphosphate analog used in this process can be prepared from the corresponding imidodiphosphate in which OH is replaced by Cl, by reaction with oxalyl chloride.

 The reaction leading to the imido-methylene triphosphate analog can be carried out by reaction of the lithiated anion (n-BuLi) of

on the imidodiphosphate chloride described above.

The product obtained by this reaction is a triphosphate analog in which all of the positions R ¹ , R ² , R ³ , R ⁴ and R ⁵ are occupied by hydrocarbon groups.

Also, we can perform a selective monoprotection to eliminate some of these hydrocarbon groups and replace them with a hydrogen atom or carry out a total deprotection to replace all these hydrocarbon groups with hydrogen atoms.

 As before, the deprotections can be selective when the hydrocarbon groups attached to the phosphorus atoms of the two ends are different from the hydrocarbon group attached to the central phosphorus atom and they can be carried out by the same methods. When it is desired to replace all the hydrocarbon groups with hydrogen atoms, complete deprotection is carried out by catalytic hydrogenation when all of these groups are benzyl.

The starting materials for the preparation of diphosphates of formula (I) in which X ¹ is a methylene group can also be prepared by a process which consists in reacting a chlorophosphate of formula:

GOLD

with a methylphosphonate of formula:

wherein R ' ¹ , R' ² , R ' ⁴ and R' ⁵ are aralkyl groups, alkyl groups, hydrocarbon groups having one or more ethylenic bonds or aryl groups.

The starting materials of the diphosphate analogs of formula (I) in which X ¹ is the NH group can be prepared by a process which consists in reacting the trichloro- [(dichlorophosphoryl) imido] phosphorane of formula:

with a compound of formula BnOH in which Bn is as defined above.

 The precursor pentachloride can be prepared by the method described by Emsley et al in J. Chem. Soc. A., 1971, p. 2873.

In the case of diphosphate analogs in which X ¹ represents the group NR ⁶ , these can be prepared by reaction of a compound of formula:

with an alcohol of formula R ' ¹ OH.

In both cases, it is then possible to carry out a monodeprotection or a total deprotection of the compound obtained by the techniques described above in order to replace if necessary the R ′ ¹ by the desired groups R ¹ , R ² , R ³ and R ⁴ .

To prepare the analogs of diphosphates and triphosphates of formula (I) in which R ⁵ represents a group derived from nucleoside, it is possible to react a compound of formula:

in which R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² and n have the meanings given above with a nucleoside of formula:

in which B is an optionally substituted pyrimidine or purine base, P ¹ and P ² are protective groups or hydrogen atoms and P ³ is a protective group, and then remove the protective group (s) if necessary (s).

 Other characteristics and advantages of the invention will appear better on reading the examples which follow, which are of course given by way of illustration and not limitation.

 Example 1: Preparation of tribenzylmethylene methylene bis phosphonate. (compound n ° 1).

0 a) Preparation of dibenzylmethyl phosphonate of formula

To a suspension of 4.57 g (114.4 mmol,

1.2 eq.) Of NaH (60% in oil) in 300 mml of anhydrous tetrahydrofuran (THF) at -15 ° C., 25 g (95.3 mmol, leq) of dibenzylhydrogenophosphite dissolved in 50 ml of anhydrous THF are added dropwise . The medium is stirred at room temperature for half an hour and cooled to -40 ° C before adding dropwise 7.2 ml of iodomethane (114.4 mmol, 1.2 eq). After a quarter of an hour, the solution is warmed to room temperature and stirred for another hour. The excess hydride is hydrolyzed by adding a saturated aqueous NH4Cl solution and the mixture is extracted twice with ethyl acetate. After drying and evaporation of the organic phases, the residue is purified by chromatography on a silica column (ethyl acetate / hexane: 80/20 to 100/0); 20 g of a colorless oil are thus obtained, which corresponds to a yield of 76%.

 The characteristics of this product are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCl ₃ ) 200 MHz

δ (ppm): 7, 36-7, 30 (m, 10H, aromatic protons); 5.01 (part AB, system ABX, J ^AB = 11.8 Hz, J _AX = 8.9Hz, J _BX = 8.5Hz, vA = 5.06, vB = 4.95, 4H, Ha); 1.46 (d, ² J _HP = 17.6Hz, 3H, Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz δ (ppm): 136.03 (d, ³ J _CP = 4, 65Hz, 1Cb);

135.93 (d, ³ J _CP = 5.7 Hz, 1Cb); 128, 06 (4Cd); 127.75 (2Ce); 127.33 (4Cc); 66.57 and 66.45 (2Ca); 11.07 (d, ¹ J _CP = 147.2 Hz, Cf).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 32.39 (s).

IR (pure, film) cm ^-1 :

 3064; 3032; 2891; 1497; 1456; 1311; 1244. b) Preparation of benzylmethylchlorophosphate of formula:

To a solution of 5 g (26.86 mmol, leq), of benzylmethylhydrogenophosphite of formula:

, in 100 ml of anhydrous CCI ₄ , cooled to -15 ° C, 6.47 ml (80.58 mmol, 3 eq) of sulfuryl chloride is added dropwise. After 15 min, the reaction mixture is heated. at room temperature and shake it again for 10 min. After evaporation of the solvent under vacuum, the residue is taken up with twice 20 ml of anhydrous toluene, which gives 5.92 g of a colorless oil which can be used without any purification (yield of 100%).

 The characteristics of this compound are as follows:

CCM:

Rf = 0.8 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7.51-7.27 (m, 5H, aromatic protons); 5, 21 (part AB, system ABX, J _AB = 11, 4HZ, J _AX = 9.1Hz, J _BX = 9Hz, vA = 5.26, vB = 5, 17, 2H, Ha); 3.89 (d, ³ J _HP = 13.8 Hz, 3H, Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 134.23 (d, ³ J _CP = 7, 9Hz, 1Cb);

128.97 (2Cd); 128.64 (1Ce) 128, 14 (2Cc); 71.04 (d, ² J _CP = 6.9 Hz, 1Ca); 55.46 (d, ² J _CP = 6.9Hz, 1Cf).

 c) Preparation of tribenzylmethylmethylene bisphosphonate.

To a solution of 10 g (36.2 mmol, 2 eq) of the dibenzylmethylphosphonate prepared in a), in 150 ml of anhydrous THF, cooled to -78 ° C., 22.62 ml of n-butyllithium are added dropwise (1.6mol solution / l) in hexane, (36.2 mmol, 2 eq.). The mixture is stirred for 15 min at -78 ° C and a yellow color appears. At -78 ° C., 4 g (18, lmmol, leq.) Of benzylmethylchlorophosphate prepared in b) are rapidly added, dissolved in 30 ml of anhydrous THF. After half an hour at -78 ° C, the reaction mixture is neutralized by the addition of an aqueous solution saturated with NH ₄ Cl, then the organic phase is extracted twice with ethyl acetate. After drying, evaporation of the organic phases under vacuum and chromatography of the residue (ethyl acetate / hexane: 70/30), 5.41 g of the compound are obtained n ° 1 in the form of a colorless oil (yield 65%).

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.3 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.35-7.27 (m, 15H, aromatic protons); 5.19-4.96 (m, 6H, H _a H _a 'and H _a "); 3.68 (d, ³ J _HP = 11.4 Hz, 3H, H _f ); 2.50 (t , ² J _HP = 21, 1 Hz, 2H, H _g ).

¹³ C NMR: (CDCI ₃ ) 50 MHz

δ (ppm): 136.07 (d, ³ J _CP = 6.5 Hz, 1C _b , 1C _{b '} , 1C _{b "} ); 128.58 (2C _C, 2C _d', 2C _d" ); 128.45 (1C _e, 1C _e ,, 1C _{e "} ,); 128.09 (2C _C, 2C _{C ',} 2C _C "); 68.21 (d, ² J _{C- P} = 5.5 Hz, 1C _a and 1C _{a '} ); 68.16 (d, ² J _CP = 6.6Ηz, 1C _a "); 52.98 (d, ² J _CP = 6.5 Hz, 1C _f ); 25.82 (t, ¹ J _CP = 136 Hz , 1Cg).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 21.43 (s) and 20.19 (s).

SM: (lC / CH ₄ )

m / z: 461 (MH ⁺ ).

IR (pure, film) cm ^-1

 3090; 3030; 2955; 2890; 1497; 1465; 1380; 1250; 1180; 1010.

 Example 2: Preparation of the acid

(dibenzylphosphinyl) (benzyl) methylenephosphonic

 (compound n ° 2).

To a solution of 5 g (10.86 mmol, leq.) Of compound n ° 1 in 70 ml of anhydrous DMF, 0.778 g (ll, 95 mmol, l, leq.) Of potassium cyanide is added. The mixture is stirred for 4 h at 70 ° C. DMF is removed by vacuum distillation of a vane pump using a Hickmann condenser. The potassium salt obtained is dissolved in 50 ml of hydrochloric acid diluted to 5%. The aqueous phase is extracted three times with ethyl acetate and once with methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated in vacuo. 4.6g of compound 2 are thus obtained in the form of a yellow oil which can be used without any purification (yield 95%).

 The characteristics of compound 2 are as follows:

CCM:

Rf = 0.3 (CH ₂ Cl ₂ / MeOH: 80/20).

¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.36-7.28 (m, 15H, aromatic protons); 5.1 (d, ³ J _HP = 11.9 Hz, 2H, H _{a '} ); 5.02 (d, ³ J _HP = 12 Hz, 4H, H _a ); 2.57 (t, ² J _HP = 21.1 Hz, 2H, H _f ). ¹³ C NMR: (CDCI ₃ ) 50 MHz

δ (ppm): 136.21 (d, ³ J _CP = 7 Hz, 1C _b ,); 135.86 (d, ³ J _CP = 6.5 Hz, 2C _b ); 128.36 (4C _d ) 128.31 (2C _d ,); 128.23 (2C _e ); 128.02 (1C _e ,); 127.87 (4C _C ); 127.46 (2C _C ,); 68.11 (d, ² J _CP = 6.5 Hz, 2C _a ); 67.30 (d, ² J _CP = 6 Hz, 1C _a ,); 26.06 (t, ¹ J _CP = 134.5 Hz, 1C _f ).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 22.06 (d, ² J _PP = 6.2 Hz) and 19.79 (d, ² J _PP = 6.2 Hz).

SM: (IC / NH ₃ )

m / z: 446.1 (MH ⁺ ),

IR (pure, film) cm ^-1 : 3400-2400; 1607; 1497; 1455; 1380; 1260; 1180; 1016; 910.

Example 3: Preparation of (dibenzylphosphinyl) (benzyl) (chloro) methylene-phosphonic (compound No. 3).

To a solution of 2 g (4.48 mmol, leq.) Of compound No. 2 in 40 ml of anhydrous benzene, 1.17 ml (13, 44 mmol, 3 eq.) Of oxalyl chloride and a drop of DMF are added dropwise anhydrous. The mixture is stirred for 2 hours at room temperature. The solution is reduced in vacuo and taken up three times with 20 ml of anhydrous toluene. 2.07 g of compound 3 are thus obtained in the form of a light yellow oil (100% yield).

 The characteristics of compound 3 are as follows:

¹ H NMR: (CDCI ₃ ) 200 MHz δ (ppm): 7.37-7.27 (m, 15H, aromatic protons); 5.22 (part AB, system ABX, J _AB = 10.3 Hz,

J _AX = 8.9 Hz, J _BX = 9 Hz, ν _A = 5.26, ν _B = 5.17, 2H, H _a ,); 5.05

(m, 4H, H _a ); 2.84 (t, ² J _HP = 21.1 Hz, 2H, H _f ).

Example 4: Preparation of benzyl bis (dibenzylphosphonomethyl) phosphinate (compound No. 4).

a) Preparation of benzyl bis (chloromethylene) phosphinate of formula

To 20 g (110.3 mmol, 1 eq.) Of bis (chloromethylene) chlorophosphinate dissolved in 400 ml of anhydrous ether at 0 ° C., 16.9 ml (121.3 mmol, 1.1 eq.) Of anhydrous triethylamine are added. Then added in 15 minutes, 13.11 g (121.3 mmol, 1.1 eq.) Of benzyl alcohol in 50 ml of anhydrous ether. After one hour at 0 ° C., the solution is warmed up to the temperature ambient and stirred for one hour. The precipitate formed is filtered, the filtrate is evaporated in vacuo and chromatographed (ethyl acetate / hexane: from 60/40 to 100/0); 24.6 g of a colorless oil are thus obtained (yield 88%).

 The characteristics of this product are as follows:

CCM:

Rf = 0.5 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.45-7.37 (m, 5H, aromatic protons); 5.19 (d, ³ J _HP = 9.3 Hz, 2H, H _a ); 3.66 (AB part, ABX system, J _{AB =} 12.5 Hz, J _AX = 7.5 HZ, J _BX = 8.1 Hz, v _A = 3.72, v _B = 3.60, 4H , Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 134.93 (d, ³ J _CP = 5.1Hz, 1Cb);

128.63 (1Ce); 128.40 (2Cd); 127.97 (2Cc);

67.73 (d, ² J _CP = 6.5 Hz, 1Ca); 32.63 (d, ¹ J _CP = 104, 7Hz, 2Cf).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 41.25 (s).

IR (CH ₂ CL ₂ ) cm ^-1 :

 3091; 3050; 3000; 2950; 2895; 1498; 1456; 1393; 1262; 1200; 1110; 1007; 847.

 b). Preparation of tribenzyl phosphite of formula:

, To a solution of 25ml (286.5 mmol, 1 eq.) Of phosphorus trichloride in 1.5 liters of anhydrous ether, cooled to -78 ° C, 123.8 ml (888) is added dropwise over ten minutes. , 3 mmol, 3.1 eq.) Of anhydrous triethylamine. The reaction medium is then treated dropwise with 92.95 g (859.6 mmol, 3 eq.) Of benzyl alcohol dissolved in 300 ml of ether. After 2 hours, the solution is warmed to room temperature and stirred under argon for 8 hours. The precipitate formed is filtered, the solvent is evaporated in vacuo, and the residue is chromatographed on a silica column (ethyl ether / hexane / trietylamine: 40/60/1); 90 g of a colorless oil are thus obtained (yield: 89%).

 The characteristics of the product obtained are as follows:

CCM

Rf = 0.5 (Et ₂ O / hexane / Et ₃ N: 50/50/1).

¹ H NMR: (CDCl3) 200 MHz

δ (ppm): 7.37 (m, 15H, aromatic protons); 4.94 (d, ³ J _HP = 8 Hz, 6H, Ha).

¹³ C NMR: (CDCl ₃ ) 50 MHz

δ (ppm): 138.21 (3C _b ); 128.37 (6C _d ); 127, 67 (3C _e ); 127.49 (6C _C ); 64.47 (d, ² J _CP = 11.1 Hz, 3C _a ).

³¹ P NMR: (CDCl ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 20.17 (s).

IR (pure film) cm ^-1

 3088; 3063; 3031; 2940; 2874; 1606; 1497; 1454;

1375; 1211; 994; 787. c) Preparation of compound 4 To 8 g (31.61 mmol, eq. Of benzyl bis (chloromethylene) phosphinate obtained in a), 44.5 g (126.4 mmol, 4 eq.) Of tribenzyl phosphite obtained in b) are added. The mixture is heated under vacuum to 140 ° C under 4 mm of mercury. And it is subjected to violent stirring in order to continuously remove the benzyl chloride. After 10 hours of stirring, the reaction mixture is chromatographed on a silica column (Et 2 O / ethyl acetate / Ethanol: from 100/0/0 to 0/80/20); 15.8 g of compound 4 are thus obtained in the form of a colorless oil (yield of 71%).

The characteristics of compound No. 4 are as follows:

CCM:

 Rf = 0.4 (AcOEt).

1 H NMR: (CDCl ₃ ) 200 MHz

δ (ppm): 7.32-7.28 (m, 25H, aromatic protons); 5.13-4.95 (m, ^3J Hp = 8.5 Hz, 10 H, H _a and H _a ,); 2.84 (dd, ^2J H-pβ = 20.3 Hz, ^2J H-Pα = 18.2 Hz, 4H _f ).

¹³ C NMR: (CDCl3) 50 MHz

δ (ppm): 135.77-135.57 (m, ^3J CP = 7.5 Hz, 4C _b , and 1C _b ,); 128.75-127.53 (8C _d , 2C _d ,, 8C _c , 2C _c ,,

4C _e , 1C _e ,); 67.95 and 67.72 (2d, ^2J CP = 6.2 Hz, 4C _a );

66.79 (d, ^2J CP = 6.5 Hz, 1C _a ,); 28.65 (dd, ^1J CP = 130 Hz,

^1J CP = 87.5 Hz, 2C _f ). ³¹ P NMR: (CDCl3 / H3PO4) 121.44 MHz

δ (ppm): 38.47 (t, ^2J Pα-Pβ ^{= 4'5} Hz, Pα) and 20.90 (d, ^2J Pα-pβ ^{= 4.5} Hz, _2pβ)

SM: (IC / NH ₃ )

m / z: 721.8 (MNH ₄ +). IR (pure, film) cm ^-1

 3088; 3063; 3033; 2954; 2894; 1497; .1468; 1380; 1250; 1182; 998.

Example 5. Preparation of (methyl) (trialyl) methylenebisphosphonate (compound No. 5).

The same procedure is followed as in Example 1 to prepare this compound starting from the diallyl methyl phosphonate of formula:

C ₇ HOPP,

and allyl methyl chlorophosphate of formula:

C ₄ O ₃ PP,

 Compound 5 is thus obtained with a yield of 60%

The characteristics of this compound are as follows: CCM:

Rf = 0.5 (CH ₂ Cl ₂ / MeOH: 95/5).

¹ H NMR: (CDCl ₃ ) 200 MHz

δ (ppm): 5.95 (m, 3H, H _b , H _b , and H _{b "} ); 5.31 (m, 6H, H _c , H _{c '} and H _c" ); 4.60 (m, 6H, H _a , H _{a '} and H _{a "} ); 3.79 (d, ^3J HP = 11.3 Hz, 3H, H _e ); 2.50 (t, ^2J HP = 21 , 1 Hz, 2H, Hd).

¹³ C NMR: (CDCl ₃ ) 50 MHz

δ (ppm): 132, 75 (d, ^3J CP = 6.6 Hz, 1C _b , 1C _{b '} , lC _{b "} ); 118.27 (1C _c , 1C _c' , 1C _c" ); 67.03 (d, ^2J CP = 6.1 Hz, 1C _a , 1C _{a '} , 1C _{a "} ); 53.03 (d, ^2J CP = 6.45 Hz, 1Ce); 25.50 (t, ^1J CP = 139 Hz, 1Cd). IR (pure, film) cm-1

 3090; 3030; 2985; 2948; 2890; 1730;

1649; 1459; 1423; 1370; 1311; 1225; 1050; 986.

 Example 6: Preparation of (triallyl) methylene diphosphonic acid (compound No. 6.

The same procedure is followed as in Example 2 to prepare this compound from compound No. 5 obtained in the previous example. Compound No. 6 is thus obtained with a yield of 98%. The characteristics of compound 6 are as follows:

CCM:

Rf = 0.5 (CH ₂ Cl ₂ / MeOH: 65/35).

¹ H NMR: (CD ₃ OD) 200 MHz

δ (ppm): 6.01 (m, 3H, Hb, Hb 'and Hb "); 5.32 (m, 6H, Hc, Hc' and Hc"); 4.66 (m, 4H, Ha and Ha '); 4.47 (m, 2H, Ha "); 2.49 (t, ² J _HP = 20, 1Hz, 2H, Hd).

¹³ C NMR: (CD ₃ OD) 50MHz

δ (ppm): 136.18 (d, ³ J _CP = 7.1 Hz, 1Cb ");

134.28 (d, ³ J _CP = 6.6 Hz, 1Cb and 1Cb '); 119, 59 (Ce and Ce '); 116.72 (Ce "); 68, 52 (d, ² J _CP = 6, 3 Hz, 1Ca and 1Ca'); 66.77 (d, ² J _CP = 6 , 1 Hz, 1Ca "); 25, 48 (t, ¹ J _CP = 140 Hz, 1Cd).

Example 7: Preparation of benzyl (dibenzylphosphonomethyl) (chloromethyl) phosphinate.

The tribenzylphosphite obtained in Example 4b) is reacted with the benzyl bis (chl (romethylene) phosphinate obtained in Example 4a), under vacuum, at 140 ° C. under 14 mm of mercury, and compound No. 7 is thus obtained with a yield of 20%.

 This yield could be increased by using less phosphite.

 The characteristics of this compound are as follows:

 CCM:

 Rf = 0, 6 (AcOEt).

¹ H NMR: (CDCl ₃ ) 200 MHz

 δ (ppm): 7.40-7.32 (m, 15H, aromatic protons); 5.19-4.94 (m, 6H, Ha, Ha 'and Ha ");

3, 66 (part AB, ABX system, J _AB = 14Hz, J _AX = 7.4Hz, J _BX = 9.4

Hz, v _A = 3.74, v _B = 3.59, 2H, Hg); 2.62 (m, 2H, Hf).

¹³ C NMR: (CDCl ₃ ) 50 MHz

 δ (ppm): 135, 61-135, 29 (1Cb, 1Cb ', 1Cb ");

128.59-127.98 (2Cd, 2Cd ', 2Cd ", 1Ce, 1Ce', 1Ce", 2Cc,

2Cc 'and 2Cc "); 68.25 (d, ² J _CP = 6, 2Hz, 1Ca);

67, 97 (d, ² J _CP = 6.3 Hz, 1 Ca '); 67, 39 (d, ² J _CP = 6.4Hz, 1Ca ");

36.05 (d, ¹ J _CP = 102.6 Hz, 1 Cg); 25.55 (dd, 1J _CP = 134, 4Hz, ¹ J _CP = 88.5Hz, 1Cf).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 39.88 (s, Pα) and 20.04 (s, Pβ).

SM: (lC / CHN ₃ )

m / z: 496.1 (MNH ₄ ⁺ ).

IR (pure, film) cm ^-1 :

 3034; 2955; 2893; 1498; 1456; 1379; 1255;

1213; 1176; 998; 836; 734.

Example 8 Preparation of bis (dibenzylphosphonomethyl) phosphinate of (α-tert-butyl) -benzyl (compound No. 8).

a) preparation of (α-tert-butyl) -benzyl (bis) chloromethylene) phosphinate of formula:

The same procedure is followed as in Example 4a) to prepare this compound using the

2,2-dimethyl-1-phenyl-1-propanol instead of benzyl alcohol, adding 0.5 eq. of DMAP and bringing the reaction mixture to reflux. The yield is

61%.

 The characteristics of this compound are as follows:

 CCM:

 RF = 0.5 (Et2O / Hexane: 70/30).

¹ H NMR: (CDCI ₃ ) 200MHz δ (ppm): 7.29 (m, 5H, aromatic protons);

5.18 (d, ³ J _HP = 9 Hz, 1H, Ha); 3.75 (d, ² J _HP = 8.7Hz, 2H, Hf);

3, 20 (part AB, ABX system, J _AB = 14.2Hz, J _AX = 8.4Hz,

J _BX = 9.2 Hz, vA = 3.27, vB = 3, 13, 2H, Hf); 0.94 (s, 9H, tert-butyl).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 137, 30 (1Cb); 128.37 (1Ce); 127.77 (2Cd); 127.69 (2Cc); 89, 26 (d, ² J _CP = 7.4Hz, 1Ca); 35.84 (d, ³ J _CP = 6.1 Hz, 1 Cg); 33, 02 (d, ¹ J _CP = 101Hz, 1Cf); 32.80 (d, ¹ J _CP = 110.6Hz, 1Cf); 25.66 (3Ch).

IR (CH ₂ Cl ₂ ) cm ^-1 :

 3094; 3038; 3001; 2972; 2889; 1496; 1458; 1391; 1262; 1203; 1110; 998.

 b) preparation of compound 8:

 The same procedure is followed as in Example 4 to prepare this compound No. 8 from (bis-chloromethylene) phospinate of (α

-tert-butyl) -benzyl obtained previously and tribenzyl phosphite prepared in Example 4b). Compound No. 8 is thus obtained with a yield of 84%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200MHz:

δ (ppm): 7.37-7.20 (m, 25H, aromatic protons); 5.17 (d, ³ JH-P = 10.5 Hz, 1H, Ha '); 5.14-4.85 (m, 8H, Ha); 3.30-3.12, 2.88-2.55 and 2.18-1.96 (m, 4H, Hf and Hf); 0.88 (9H, tert-butyl).

³¹ P NMR: (CDCl ₃ / H ₃ PO4) 121.44 MHz

δ (ppm): .37.79 (d, ² J _PP = 8.3Hz, Pα); 21, 61 (s, P β); 21.11 (d, ² J _PP = 8.3 Hz, Pβ ').

SM: (lC / NH ₃ )

m / z: 778 (MNH ₄ ⁺ ); 761 (MH ⁺ ). Example 9: Preparation of tetrabenzylmethylene diphosphonate (compound No. 9).

a) preparation of the dibenzyl chlorophosphate of formula:

_{14 14 3}

4.36 ml (54.3 mmol, 3 eq.) Of sulfuryl chloride are added dropwise to a solution of 4.75 g (18, lmmol, 1 eq.) Of dibenzylphosphite in 50 ml of anhydrous CCI ₄ , cooled to -15 ° C. After 1/4 hour, the reaction mixture is warmed to room temperature and stirred for another 10 minutes. After evaporation of the solvent under vacuum, the residue is taken up twice with 10 ml of anhydrous toluene and 5.37 g of dibenzyl chlorophosphate are thus obtained in the form of a colorless oil which can be used without any purification (yield of 100% ).

 The characteristics of this product are as follows:

CCM: Rf = 0.8 (Et ₂ O / hexane: 80/20).

¹ H NMR: (CDCl ₃ ) 200MHz:

δ (ppm 7, 43-7, 29 (m, 10H, aromatic protons); 5, 22 (m, ³ J _HP = 7.5Hz, 4H, Ha).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 134.23 (d, ³ J _CP = 7.9Hz, 2Cb);

128.97 (4Cd); 128.64 (2Ce); 128.14 (4Cc);

71.05 (d, ² J _CP = 6.9Hz, 2Ca).

 b) Preparation of Compound No. 9

 To a solution of 10 g (36.2 mmol, 2 eq) of the dibenzylmethylphosphonate obtained in Example 1a) in 150 ml of anhydrous THF, cooled to -78 ° C., 22.62 ml of n-butyl are added dropwise lithium (1.6 mol / l solution in hexane, 2 eq.). The mixture is stirred for 1/4 hour at -78 ° C and a yellow color appears.

At -78 ° C., 5.37 g (18.1 mmol, leq.) Of the dibenzylchlorophosphate obtained previously, dissolved in 20 ml of anhydrous THF, are quickly added. After half an hour at -78 ° C., the reaction mixture is neutralized by the addition of an aqueous solution saturated with NH ₄ Cl, then the organic phase is extracted twice with ethyl acetate and once with chloride. methylene. After drying, evaporation under vacuum of the organic phases and chromatography of the residue (ethyl acetate / hexane: 80/20 to 100/0), 4.84 g of compound No. 9 is obtained in the form of a colorless oil

(50% yield).

 The characteristics of this product are as follows:

CCM:

 Rf = 0.45 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200MHz: δ (ppm): 7.32-7.29 (m, 20H, aromatic protons); 5.02 (d, ³ J _HP = 7.5 Hz, 8H, Ha); 2.52 (t, ² J _HP = 21.1 Hz, 2H, Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm):: 135.84 (d, ³ J _CP = 6.4 Hz, 4Cb); 128.30 (8Cd); 128.17 (4Ce); 127.80 (8Cc); 67.84 (d, ² J _CP = 5.9 Hz, 4Ca); 26.40 (t, ¹ J _CP = 135Hz, 1Cf). ³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 20.79 (s, 2P).

SM: (lC / NH ₃ )

m / z: 554 (MNH ₄ ⁺ ).

IR (pure, film) cm ^-1 :

 3070; 3063; 3033, 2953; 2898; 1497; 1468; 1380; 1250; 1182; 998.

 Example 10: Preparation of bis (dibenzylphosphinyl) benzylamine (compound No. 10).

a) preparation of bis (dichlorophosphinyl benzylamine of formula:

_{7 7 2} To 7 g (45.65 mmol, 2 eq.) Of freshly distilled phosphorus oxychloride in 100 ml of anhydrous THF at -78 ° C. are added 6.68 ml (47.93 mmol, 2.1 eq.) Of anhydrous triethylamine . Then, 2.49 ml (22.82 mmol, 1 eq.) Of benzylamine in 50 ml of anhydrous THF are added dropwise over 3 hours. The mixture is left to return to -50 ° C., then stirred for 15 minutes. The precipitate formed is filtered, the solvent is evaporated and a yellow syrup is obtained containing triethylamine salts. The syrup is taken up in 300 ml of anhydrous THF, the precipitate formed is again removed by filtration, the filtrate is evaporated under vacuum to give 7 g of a light yellow oil

(yield: 90%).

¹ H NMR: (CDCI ₃ ) 200MHz:.

δ (ppm): 7, 48-7, 26 (m, 5H, aromatic protons); 5.05 (t, ³ J _{H- P} = 18, 3Hz, 2H, Ha),

 b) preparation of compound No. 10

To a suspension of 3.45 g (86.23 mmol, 4.2 eq.) Of NaH (60% in oil) in 400 ml of anhydrous THF at 0 ° C., 8.88 g are added dropwise (82.12 mmol, 4 eq.) Benzyl alcohol in 50 ml of anhydrous THF. The mixture is allowed to return to room temperature for 1/2 hour, then it is added dropwise to a solution of 7 g (20.53 mmol; 1 eq.) Of the bis (dichlorophosphinyl) benzylamine obtained above in 200 ml of anhydrous THF, at -78 ° C. After 1 hour at -78 ° C, the solution is warmed to room temperature and stirred for 1 hour, then cooled to 0 ° C. The excess hydride is hydrolyzed and the medium is neutralized with a solution of hydrochloric acid diluted to 5%. The reaction mixture is then half evaporated and extracted 3 times with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated in vacuo. We chromatography the residue obtained on silica (ethyl ether / hexane: from 50/50 to 100/0); 7.47 g of compound 10 are thus obtained in the form of a colorless oil (yield of 58%).

 The characteristics of this compound are as follows:

CCM:

Rf = 0.5 (Et ₂ O / hexane: 90/10).

¹ H NMR: (CDCI ₃ ) 200MHz:

δ (ppm): 7.57-7.52 (m, 2H, aromatic protons); 7, 34-7, 18 (m, 23H, aromatic protons); 4.93 (part AB of an ABXM, J _AB = 13.7 Hz, J _AX = 7.5 Hz, J _BX = 7.4Hz, J _AM = 2.4Hz, 8H, Ha); 4.64 (t, ³ J _HP = 13.9 Hz, 2H, Ha ').

¹³ C NMR: (CDCl ₃ ) 50MHz

δ (ppm): 138, 10 (1Cb '); 135.80-135, 64 (4Cb); 128, 84-128, 34-128, 23-128, 10 (8Cd, 2Cd ', 4Ce, 1Ce', 8Cc and 2Cc '); 68.73 (d, ² J _CP = 5.5Hz, 4Ca); 50.76 (1Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 4.88 (s).

SM: (IC / NH ₃ )

m / z: 645.1 (MNH ₄ ⁺ ); 628 (MH ⁺ ).

IR (pure, film) cm ^-1 :

 3063; 3033, 2951; 2892; 1497; 1455 1378; 1275; 1214; 1010; 970; 890.

 Example 11 Preparation of the Acid

(N-benzyl) (tribenzyl) imidophosphorique (compound n ° 11).

This compound is prepared from compound No. 10 by carrying out deprotection with DABCO (1,4-diazabicyclo [2,2,2] octane.

 For this purpose, 0.318 g of DABCO (2.84 mmol, 1 eq.) Is added to 1.78 g of compound 10

(2.84 mmol, 1 eq.) Dissolved in 10 ml of anhydrous toluene. The reaction mixture is brought to reflux for 2 hours. The solution is reduced in vacuo and the salt obtained is dissolved in 50 ml of hydrochloric acid diluted to 5%. The aqueous phase is extracted 3 times with ethyl acetate and once with methylene chloride. The organic phases are combined, dried over sodium sulfate and evaporated in vacuo. Compound No. 11 is thus obtained with a yield of 97%.

 The characteristics of this compound are as follows:

¹ H NMR: (CDCI ₃ ) 200MHz:

δ (ppm): 7, 6-7.1 (m, 20H, aromatic protons); 5.15-4.8 (m, 6H, Ha and Ha '); 4.55 (t, ³ J _HP = 14Hz, 2H, Ha ").

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 136.23 (1Cb "); 136, 55 (d, ³ J _CP = 8Hz, 1Cb '); 135, 75 (d, ³ J _CP = 7, 7Hz, 2Cb); 128, 55- 127, 22 (4Cd, 2Cd ', 2Cd ", 4Cc, 2Cc', 2Cc", 2Ce, 1Ce ', 1Ce "); 68.75 (d, ² J _CP = 5.1 Hz, 2Ca); 68.05 (d, ² J _CP = 4.7Hz, 1Ca "); 50.48 (1Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 5.78 (d, ² J _PP = 27.6Hz) and 3.92 (d, ² J _PP = 27.6Hz).

SM: (lC / NH ₃ )

m / z: 554.9 (MNH ₄ ⁺ ).

IR (pure, film) cm ^-1 :

3112-2330; 1488; 1440; 1384; 1265; 1221; 1084; 1028. Example 12: Preparation of benzyl (dibenzyl phosphonomethyl) (benzyl hydrogenophosphonomethyl) phosphinate (compound No. 12).

0

To 0.796 g of DABCO (7.09 mmol, leq), 5 g of compound No. 4 (7.09 mmol, 1 eq) dissolved in 70 ml of anhydrous toluene are added. The reaction mixture is brought to reflux for 2 hours. The solution is reduced in vacuo and the salt obtained is dissolved in 100 ml of a water / methanol mixture (30/70). To the above solution, an ion exchange resin loaded with H ₃ O ⁺ ions (Dowex 50X8) is added and then stirred for 12 hours. The resin is recovered by filtration, the filtrate is concentrated and it is taken up 3 times with 100 ml of toluene. 4.18 g of compound No. 12 are thus obtained in the form of a yellow oil which can be used without any purification (yield of 96%). The characteristics of compound 12 are as follows

¹ H NMR: (DMSO d6) 200MHz:

δ (ppm): 7, 37-7, 31 (m, 20H, aromatic protons); 5.07 (d, ³ J _HP = 7.2 Hz, 2H, H benzyls); 4.97 (d, ³ J _HP = 7.4 Hz, 6H, benzyl H); 2.77 (t, ² J _HP = 20.1 Hz, 4H, Hf).

¹³ C NMR: (CD ₃ OD) 50MHz

 δ (ppm): 137, 82-137, 38 (2Cb, 1Cb ', 1Cb "); 129, 60-128, 85 (4Cd, 2Cd', 2Cd", 2Ce, 1Ce ', 1Ce ", 4Cc, 2Cc' , 2Cc "); 69.45 (d,

² J _CP = 5.7Hz); 68.75 (d, ² J _CP = 5.7Hz); 68, 33 (d, ² J _CP = 6, 3Hz) (2Ca, 1Ca 'and 1Ca "); 29, 62 (dd, ¹ J _CP = 87.1Hz and ¹ J _CP = 130, 6Hz, 2Cf).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 41.21 (d, ² J _PP = 4.7 Hz, Pα) and 18.59 (d, ² J _PP = 5.08 Hz, Pβ and Pβ ').

SM: (IC / NH ₃ )

m / z: 631.9 (MNH ₄ ⁺ ); 524, 2 (M-Bn + H ⁺⁾ .

IR (pure, film) cm _-1:

 3064-2300; 1693; 1610; 1498; 1455; 1382; 1215; 997; 854; 734.

 Example 13: Preparation of (dibenzylphosphonomethyl) (benzyl potassium phosphonomethyl) α - (tert-butyl) -benzyl phosphinate (compound no. 13).

0.590 g of DABCO (5.26 mmol, leq.) Is added to 4 g of compound No. 8 (5.26 mmol, 1 eq.) Dissolved in 60 ml of anhydrous toluene. The reaction mixture is brought to reflux for 2 hours. The solution is reduced in vacuo, and the salt obtained is dissolved in 90 ml of a water / methanol mixture (30/70). To the above solution, an ion exchange resin loaded with K ⁺ ions (Dowex 50 × 8) is added, then the mixture is stirred for 12 hours. The resin is recovered by filtration, the filtrate is concentrated and it is taken up three times with 100 ml of toluene. 3.68 g of compound 13 are thus obtained in the form of a yellowish solid which can be used without any purification (yield of 99%).

 The characteristics of this compound are as follows:

¹ H NMR: (CD ₃ OD) 200MHz:

 δ (ppm): 7, 32-7, 26 (m, 20H, aromatic protons); 5.17-4.7 (m, 7H, Hbenzyls); 2.75-1.7 (m, 4H, Hf and Hf); 0.90 and 0.88 (9H, tert-butyl).

SM: -lC / NH ₃ )

m / z: 709 (MH ⁺ ); 705 (MK ⁺ + 2NH ₄ ⁺ );

615 (MK ⁺ -Bn + 2NH ₄ ⁺ + H ⁺ ).

Example 14: Preparation of benzyl (dibenzyl phosphonomethyl) (benzyl methyl phosphonomethyl) phosphinate (compound No. 14).

 To 8 g (16.70 mmol, 1 eq.) Of compound No. 7, 18.46 g (66.83 mmol, 4 eq.) Of dibenzylmethylphosphite are added. The mixture is heated under vacuum (140 ° C. under 4 mm of mercury and subjected to vigorous stirring in order to continuously remove the benzyl chloride. After 10 hours of stirring, the reaction mixture is chromatographed on a silica column (ethyl ether / ethyl acetate / ethanol: from 100/0/0 to 0/70/30); 8.94 g of compound No. 14 are thus obtained in the form of a colorless oil (yield of 85% ).

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.4 (AcOEt / EtOH: 90/10).

¹ H NMR: (CDCI ₃ ) 200 MHz: mixture of diastereoisomers:

δ (ppm): 7.38-7.29 (m, 20H, aromatic protons); 5.16-4.94 (m, 8H, Ha, Ha 'and Ha "); 3.69 and 3.63 (2d, ³ J _HP = 11.5Hz, 3H, Hg); 2.87-2, 72 (m, 4H, Hf and Hf ').

¹³ C NMR: (CDCl ₃ ) 50 MHz: mixture of diastereoisomers:

δ (ppm): 135.85 (d, ³ J _CP = 6.2Hz, 2Cb, 1Cb 'and 1Cb "); 128.42-127.87 (4Cd, 4Cc, 2Cd', 2Ce, 2Cc ', 1Ce' , 2Cd ", 2Cc" and 1Ce "); 68.05 and 67.84 (2d, ² J _CP = 6.2Hz, 2Ca and 1Ca"); 66, 95 (d, ² J _CP = 6.2 Hz, 1 Ca '); 52.75 and 52.60 (2d, ² J _CP = 6.2Hz, 1Cg); 28.87 and 28.58 (2dd, ¹ J _CP = 87.3Hz and ¹ J _CP = 132.5Hz, Cf, Cf ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 38.52 (s, Pα), 21.75 (s, Pβ '); 20.89 (s, Pβ). SM: (lC / NH ₃ )

m / z: 646 (MNH ₄ ⁺ ).

 This compound can also be prepared from compound No. 12.

 In this case, 319 μl of ethyl azodicarboxylate (2.02 mmol, 2.5 eq.) Is added dropwise at room temperature to a solution of 500 mg of compound No. 12 (0.81 mmol , leq.), 36.3 μl of methanol (0.89 mmol, 1.1 eq.) and 530 mg of triphenylphosphine

(2.02 mmol, 2.5 eq.) Dissolved in 5 ml of anhydrous THF.

After 2 hours, the solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica column (ethyl ether / ethyl acetate / ethanol: from 100/0/0 to 0/70/30); 409 mg of compound No. 14 are thus obtained in the form of a colorless oil (yield of 80%).

 Example 15: Preparation of the

6-chloro-2 ', 3'-O-benzylidene 5' [tetrabenzyl-α, β: β, γ -dimethylene triphosphate] purine-9H (compound No. 15).

To a solution of 1.19 g (1.93 mmol, leq.) Of compound No. 12, 726 mg (1.93 mmol, 1 eq.) Of 6-chloro-2 ', 3'-O-benzylidene ( 5'-hydroxy) purine-9H and 1.27 g (4.82 mmol, 2.5 eq.) Of triphenylphosphine dissolved in 30 ml of anhydrous THF, 759 μl (4.82 mmol, 2, 5 eq.) Of ethyl azodicarboxylate at room temperature. After 1 hour, the solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica column (ethyl ether / ethyl acetate / ethanol: from 100/0/0 to 0/90/10); 1.32 g of compound 15 are thus obtained in the form of a white powder (yield of 70%).

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt / EtOH: 95/5).

F ° = 49-50 ° C

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

δ (ppm): 8.75-8.46 (m, 2H, H ₈ and H ₂ ); 7, 61-7.2 (m, 25H, aromatic protons); 6.41-6.27 (4d, ³ J _H1'-H2 , = 2.6Hz, 1H, H1 '); 6.01-5.94 (6s, 1H, Hf); 5.58-5.52 (m, 1H, H2 '); 5.40-5.33 (m, 1H, H ₃ ,); 5.30-4.85 (m, 8H, Ha, Ha 'and Ha "); 4.60 (m, 1H, H ₄ ,); 4.38-4.04 (m, 2H, H5'); 2.95-2.55 (m, 4H, Hk and Hk ').

¹³ C NMR: (CDCI ₃ ) 50 MHz, mixture of diastereoisomers:

δ (ppm): 151.58 (1C ₆ ); 151.15-150.96 (1C ₂ and 1C4); 144, 44-144, 35 (1C8); 135, 66-135, 18 (2CblCb ', 1Cb "and 1Cg); 132, 08-131, 39 (1C5); 129, 88-129, 87 (2Ce, 1Ce ', 1Ce "and 1Cj), 128, 52-127, 92 (4Cd, 2Cd', 2Cd", 4Cc, 2Cc ', 2Cc ", 2Ch and 2Cj); 107, 92 (1Cf);

90, 70-90, 58 (1C1 '); 90, 23-90, 22 (1C4 ');

 85, 05-84, 44 (1C2 '); 82, 05-81, 78 (1C3 '); 68, 41-61, 83 (2Ca, 1Ca ', 1Ca "and 1C5'); 30, 76-25, 70 (1Ck and 1Ck ').

SM: (lC / NH ₃ ) m / z: 633.1 (M-357 + H ⁺ + NH ₄ ⁺ ); 614.9 (M-373 + H ⁺ + NH ₄ ⁺ ).

IR (CCl ₄ ) cm ^-1 :

 3088; 3063; 3033; 2954; 2894; 1593; 1505; 1468; 1380; 1250; 1108; 1074.

 Example 16: Preparation of 6-azido-2 ', 3'-0-benzylidene 4,5' - [tetrabenzyl α, β: β, γ-dimethylene triphosphate] purine-9H. (compound n ° 16)

To a solution of 1.19 g (1.93 mmol, leq.) Of compound No. 12, 738 mg (1.93 mmol, 1 eq.) Of 6-azido-2 ', 3'-0-benzylidene (5 '-hydroxy) purine-9H and 759 μl (4.82 mmol, 2.5 eq.) Of ethyl azodicarboxylate dissolved in 20 ml of anhydrous THF, 1.27 g (4.82 mmol, 2.5 eq.) Of triphenyl phosphine dissolved in 10 ml of anhydrous THF. After one hour, the solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica column (ethyl ether / ethyl acetate / ethanol: from 100/0/0 to 0/90/10); 755 mg of compound No. 16 are thus obtained in the form of a white powder (yield of 40%).

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt / EtOH: 90/10).

F ° = 51-52 ° C.

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

 δ (ppm): 9.5 (m, 1H, H8); 8.75-8.30 (m, 1H, H2); 7, 61-7, 23 (m, 25H, aromatic protons); 6.51-6.27 (m, 1H, H1 '); 6, 02-5, 93 (6s, 1H, Hf); 5.60-5.51 (m, 1H, H2 '); 5.40-5.33 (m, 1H, H3 '); 5, 31-4, 85 (m, 8H, Ha, Ha 'and Ha "); 4, 75-4, 60 (m, 1H, H4'); 4, 38-4, 04 (m, 2H, H5 '); 2, 95-2, 55 (m, 4H, Hk and Hk').

IR (CCl ₄ ) cm ^-1 :

 3090; 2941; 2884; 2115; 1640; 1505; 1223; 1274; 1110; 1074; 990.

Example 17 Preparation of Bis (Dihydroxyphosphonylmethyl) Phosphinic Acid (Compound No. 17)

A 303 mg (0.43 mmol, 1 eq.) Of compound No. 4 and 30 mg (10% by mass) of Pd-C (10%) dissolved in 10 ml of a methanol / water mixture (80/20) , 1.35 g (21.50 mmol, 50 eq.) of ammonium formate are added. The mixture is brought to reflux for 90 minutes. After filtration of the Pd-C and evaporation of the solvents under reduced pressure, the residue is dissolved in 20 ml of methanol. The product is precipitated with 10 ml of acetone, centrifuged, then dried. 103 mg of compound No. 17 are thus obtained in the form of a very hygroscopic white powder (yield of 95%).

 The characteristics of this compound are as follows:

¹ H NMR: (D ₂ O) 200 MHz

δ (ppm): 2.15 (dd, ² J _H-Pβ = 20.3Hz, ² J _H-Pα =

18.2Hz, 4H).

³¹ P NMR: (D ₂ O / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 37.3 (s, Pα) and 17.5 (s, Pβ).

 Example 18: Preparation of (5'-α, β: β, γ-dimethylene) triphosphate) adenosine (compound No. 18).

At 130 mg (0.13 mmol, leq.) Of compound No. 16 and 65 mg (50% by mass of Pd-C (10%) dissolved in 5 ml of a methanol / water mixture (80/20), 820 mg is added (13 mmol, 100 eq.) of ammonium formate. The mixture is brought to reflux for 90 minutes. After filtration of the Pd-C and evaporation of the solvents under reduced pressure, the residue is dissolved in 10 ml of methanol. The product is precipitated with 5 ml of acetone, centrifuged, then dried. 63 mg of compound No. 18 are thus obtained in the form of a very hygroscopic white powder (yield of 96%).

 The characteristics of this compound are as follows:

F ° = 140-142 ° C.

¹ H NMR: (D ₂ O) 200MHZ

δ (ppm): 8.45 (S, 1H, H8); 8.14 (s, 1H, H ₂ ); 6.01 (d, ³ J _H1 , _-H2 , = 5.3 Hz, 1H, H1 '); 4.70 (H ₂ , is below the peak of D ₂ O); 4.46 (t, ³ J = 5 Hz, 1H, H3 '); 4.26 (m _. , 1H, H4 '); 4.05 (m, 2H, H5 '); 2.40-1.75 (m, 4H, Ha and Hb).

Example 19: Preparation of tetrabenzyl imidodiphosphate (compound No. 19).

To a suspension of 2.31 g (57.93 mmol), 5.2 eq.) Of NaH (60% in oil) in 100 ml of anhydrous benzene, 6 g are added dropwise

(55.7 mmol, 5 eq.) Benzyl alcohol in 50 ml of anhydrous benzene, at 0 ° C. The mixture is allowed to return to room temperature for half an hour, then 3 α (31.14 mmol. 1) is added dropwise over 30 minutes. eq.) of trichloro [(dichlorophosphoryl) imido] phosphorane (dissolved in 50 ml of anhydrous benzene, at 0 ° C. After one hour at 0 ° C., the solution is warmed to room temperature and stirred for 3 hours, then the mixture is cooled to 0 ° C. 50 ml of ether are added and the excess hydride is hydrolyzed by addition of an aqueous solution saturated with NH ₄ CI. The mixture is then evaporated to half and three extracted times with ethyl acetate The organic phase is dried over sodium sulfate and evaporated in vacuo The residue obtained is chromatographed on a silica column (ethyl ether / hexane: 50/50 to 100/0 ); 4.19 g of compound 19 are thus obtained in the form of a colorless oil (yield of 70%).

 The characteristics of this compound are as follows:

CCM:

Rf = 0.5 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7.38-7.20 (m, 20H, aromatic protons); 5.03 (d, ³ J _HP = 7.5Hz, 8H, Ha); 1.89 (s, 1H, NH).

¹³ C NMR: (CDCI ₃ ) 50MHz

δppm): 135, 10 (d, ³ J _CP = 6, 3Hz, 4Cb);

128, 09-126, 97 (8Cd, 8Cc, 4Ce); 69, 92 (d, ² J _CP = 5, 1Hz, 4Ca). Example 20 Preparation of (dibenzyl phosphinyl) (benzyl N-benzylphosphoramidyl) benzylamine (compound 20)

 178 mg of quinuclidine (1.6 mmol, 1 eq.) Are added to 1 g of compound No. 10 (1.6 mmol, 1 eq.) Dissolved in 10 ml of anhydrous toluene. The reaction mixture is brought to reflux for 45 minutes. It is cooled to 0 ° C. and treated dropwise with 280 μl (3.2 mmol, 2 eq.) Of oxalyl chloride and a drop of anhydrous DMF. The solution is warmed to room temperature and stirred for 3 hours. To remove excess oxalyl chloride, the solution is reduced by half in vacuo. 5 ml of anhydrous toluene, 268 μl (1.92 mmol, 1.2 eq.) Of anhydrous triethylamine and 175 μl (1.6 mmol, 1 eq.) Of benzylamine are then added to the preceding solution, cooled to 0 ° C. . The solution is warmed to room temperature and stirred for 2 hours. The solvent is evaporated off under reduced pressure and the residue is chromatographed on a silica column (ethyl ether / hexane: from 80/20 to 100/0); 652 mg of compound No. 20 are thus obtained in the form of a colorless oil (yield of 65%).

 The characteristics of this compound are as follows:

CCM:

Rf = 0.5 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200MHZ δ (ppm): 7.53-7.01 (25H, aromatic protons); 5.02 (d, ³ J _HP = 7.2 Hz, 2H, Ha); 4.88 (m, 2H, Hb); 4.73-4.48 (m, 2H, Hc); 4.59 (t, ³ J _Hd-P = _14.4 Hz, 2H, Hd); 4.39-4.17 (m, 2H, He); 4.03 (m, 1H, Hf).

³¹ P NMR: (CDCl ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 13.98 (d, ² J _PP = 23.2 Hz) and

5.12 (d, ² J _PP = 23.2Hz).

SM: (lC / NH ₃ )

m / z: 644.1 (MNH4 ⁺ ); 627.2 (MH ⁺ ).

Example 21 Preparation of (cyclo N, N'benzyl phosphinyl) (N, N'-dibenzyl phosphinyl) ethylenediamine (compound no. 21)

 a) preparation of (N, N'-dibenzyl phosphinyl) ethylenediamine of formula:

1 g (16.64 mmol, 1 eq.) Of ethylene diamine and 4.87 ml (34.94 mmol, 2.1 eq.) Of triethylamine are dissolved in 60 ml of anhydrous THF and the mixture is cooled to 0 ° C. . 9.87 g (33.28 mmol, 2 eq.) Of dibenzyl chhorophosphate obtained in Example 9a are added to 10 ml of anhydrous THF over 10 minutes. The reaction medium is warmed to room temperature and stirred under argon for 1 hour. The triethylammonium chloride salts formed are removed by filtration, the filtrate is reduced in vacuo and the residue is chromatographed on a silica column (ethyl acetate / ethanol: from 100/0 to 90/10); 8.4 g of (N, N'-dibenzyl phosphinyl) ethylenediamine are thus obtained in the form of a yellowish solid (yield of 87%).

 The characteristics of this product are as follows:

CCM:

 Rf = 0.5 (AcOEt / EtOH: 90/10).

¹ H NMR: (CDCI ₃ ) 200MHz

 δ (ppm): 7.31 (s, 20 H, aromatic protons);

4.99 (d, ³ J _HP = 7.8 Hz, 8H, Ha); 3.10 (m, 2H, NH); 2, 92-2, 80 (m, 4H, Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 136, 21 (d, ³ J _CP = 7, 4Hz, 4Cb); 129.01 (8Cd); 128, 00 (4Ce), 127, 53 (8Cc);

67.77 (d, ² J _CP = 5.2Hz, 4Ca); 42, 43 (d, ² J _CP = 5.5 Hz, 2Cf). SM: (lC / NH ₃ )

m / z: 598.1 (MNH4 ⁺ ); 581.2 (MH ⁺ ).

b) Preparation of the (cyclo N, N'-benzyl phosphityl) (N, N'-dibenzyl phosphinyl) ethylenediamiye of formula:

4 g of the (N, N'-dibenzyl phosphinyl) ethylenediamine obtained previously (6.89 mmol, 1 eq.), 1.92 ml (13.78 mmol, 2 eq.) Of triethylamine and 109 mg are dissolved. , 89 mmol, 0.13 eq.) Of 4-dimethylaminopyridine in 40 ml of anhydrous THF and the mixture is cooled to 0 ° C. 5.76 g (27.56 mmol, 4 eq. Of benzyldichlorophosphite dissolved in 27 ml of anhydrous THF are then added dropwise. The reaction medium is warmed to room temperature and stirred under argon for 12 hours. the precipitate formed is filtered, the filtrate is evaporated in vacuo and the residue is chromatographed on a silica column

(ethyl acetate / hexane: from 80/20 to 100/0); 3.2 g of (cyclo N, N'-benzylphosphityl) (N, N'-dibenzyl phosphinyl) ethylenediamine are thus obtained in the form of a colorless oil (yield 65%).

 The characteristics of this product are as follows:

CCM:

 Rf = 0.5 (AcOEt).

₁ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 37-7, 24 (m, 25H, aromatic protons); 5.07-4.96 (m, 8H, Ha); 4.87 (d, ³ J _HP = 8 Hz, 2H, Ha '); 3, 49-3, 19 (m, 4H, Hb).

SM: (lC / NH ₃ ) m / z: 734.4 (MNH4 ⁺ ); 717.4 (MH ⁺ ).

 c) preparation of compound No. 21

 0.82 g are added dropwise

(4.74 mmol, 1.7 eq.) Of 4-chloroperoxybenzoic acid in solution in 10 ml of CH ₂ CI ₂ to 2 g (2.79 mmol, 1 eq.) Of (cyclo N, N'- benzyl-phosphityl) (N, N'-dibenzylphosphinyl) ethylene diamine obtained previously, in

18 ml of CH ₂ CI ₂ at - 40 ° C. The reaction medium is warmed to room temperature and stirred for 4 hours. We break down the excess acid

4-chloroperoxybenzoic acid by addition of 10 ml of a saturated aqueous solution of Na ₂ S ₂ O ₅ and the solution is neutralized by adding 10 ml of a saturated aqueous solution of NaHCO ₃ . The mixture is extracted twice with ethyl acetate and once with methylene chloride. After drying and evaporation of the organic phases, the reaction crude is purified on a silica column (ethyl acetate / hexane / ethanol: from 80/20/0 to 95/0/5); 2 g of compound 21 are thus obtained in the form of a colorless oil (98% yield).

 The characteristics of compound No. 21 are as follows:

CCM

 Rf = 0.5 (AcOEt / EtOH: 97/3).

¹ H NMR: (CDCI ₃ ) 200MHz

 δ (ppm): 7, 37-7, 24 (m, 25H, aromatic protons); 5.06-4.95 (m, 8H, Ha and 2H, Ha '); 3, 51-3, 21 (m, 4H, Hb).

SM: (lC / NH ₃ )

m / z: 750.8 (MNH4 ⁺ ); 733.4 (MH ⁺ ).

Example 22 Preparation of (cyclo N, N'-benzylphosphinyl (N, N'-benzylphosphinyl) α, α'-O-xylenediamine (compound No. 22)

a) preparation of α, α'-diphtalimide-o-xylene of formula:

We bring to reflux for 2 hours 20 g

(75.77 mmol, 1 eq.) Of α, α'-dibromo-o-xylene and 29.5 g (159.11 mmol, 2.1 eq.) Of potassium phthalimide in 400 ml of anhydrous DMF. The precipitate formed is filtered on a frit, washed with water and dried under vacuum, which gives 28.2 g of α, α'-diphtalimide-o-xylene in the form of a white solid ( yield 94%).

b) preparation of α, α'-O-xylene diamine of formula:

C ₈ H ₁₂ N ₂ PM: 136.19

28.2 g (71.14 mmol) of the product obtained in a) are refluxed for 3 hours in 400 ml of hydrazine (60% in water); the solution becomes clear. The reaction mixture is cooled, evaporated in vacuo, taken up in 400 ml of water and 400 ml of concentrated hydrochloric acid are added thereto dropwise at 0 ° C. The mixture is warmed to room temperature and brought to reflux for 2 hours. It is cooled, the precipitate formed is filtered, the filtrate is evaporated under vacuum and taken up in 500 ml of water. The pH of the mixture is adjusted to 14 by adding sodium hydroxide at 0 ° C. and the solution is extracted three times with CH ₂ CI ₂ . The organic phase is dried over sodium sulfate and evaporated in vacuo; 7.95 g of α, α'-o-xylene-diamine are thus obtained in the form of a colorless oil which carbonates very quickly (yield of 82%).

 The characteristics of this product are as follows:

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 34-7, 22 (m, 4H, aromatic protons); 3.91 (s, 4H, Ha); 2.16 (s, 4H, NH ₂ ).

¹³ C NMR: (CDCI ₃ ) 50MHz

 δ (ppm): 140.50 (2Cb); 128.56 (2Cd); 127.25 (2Cc); 43.88 (2Ca).

IR (CH ₂ Cl ₂ ) cm _-1 :

 3380; 3277; 3063; 2872; 1588; 1490; 1452; 1383;

1021; 950. c) preparation of (N, N'-dibenzylphosphinyl] α, α'-o-xylene diamine of formula:

C ₃₆ H ₃₈ N ₂ O ₆ P ₂ PM: 656.65

 The same procedure is followed as in Example 21 a) to prepare this compound from the dibenzylchlorophosphate obtained in Example 9a) and from α, α'-o-xylenediamine obtained previously; thus obtaining (N, N'-dibenzylphosphinyl) g, g'-o-xylenediamine with a yield of 96%.

 The characteristics of this product are as follows:

CCM:

 Rf = 0.5 (95/5: AcOEt / EtOH).

 F ° = 85-86 ° C.

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 32-7, 15 (m, 24H, aromatic protons); 4.93 (part AB syst.ABX, J _AB = 11.8Hz, J _AX = 7.5Hz, J _BX = 7.5Hz, vA = 4.98, vB = 4.88, 8H, Ha); 4.06-3.96 (m, 6H, Ha 'and NH).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 137, 21 and 136.33 (2d, ³ J _CP = 6.2Hz, ³ J _CP = 7.3Hz, 2Cb 'and 4Cb); 129.09-127.58 (8Cd, 8Cc, 4Ce, 2Cd ', 2Cc'); 67, 79 (d, ² J _CP = 5, 1Hz, 4Ca);

42.24 (2Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

 δ (ppm): 9.72 (s, 2P).

SM: (lC / CH ₄ )

m / z: 657 (MH ⁺ ).

IR (CH ₂ Cl ₂ ) cm ^-1 :

 3409; 3237; 3090; 3052; 2980; 2953; 2891; 1889; 1812; 1719; 1497; 1455; 1416; 1379; 1283; 1239; 1080; 1027; 917; 874.

 d) preparation of the (cyclo N, N'-benzyl phosphityl) (N, N'-dibenzylphosphinyl) α, α'-o-xylenediamine of formula:

C ₄₃ H ₄₃ N ₂ O ₇ P ₃ PM: 792.74

 The same procedure is followed as in Example No. 21 a) to prepare this compound from benzyldichlorophosphite and from the (N, N'-dibenzylphosphinyl) α, α'-o-xylenediamine obtained previously. This gives (cyclo N, N'-benzylphosphityl) (N, N'-dibenzylphosphinyl) α, α '-o-xylenediamine with a yield of 45%.

The characteristics of this product are as follows: CCM:

 Rf = 0.5 (AcOEt / hexane: 70/30).

¹ H NMR: (CDCI ₃ ) 200MHZ

δ (ppm): 7.37-7.09 (m, 29H, aromatic protons); 5.25-4.79 (m, 10H, Ha and Ha '); 4.61 (dd, J = 6.5Hz, J = 11.6Hz, 2H, Ha "); 4.12 (m, 2H, Ha"). ³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 8, 36 (s. P ₁ and P ₃ ) and 7.51 (s, P ₂ ). SM: (lC / CH ₄ )

m / z: 793 (M ⁺ ).

 e) preparation of compound No. 22

 The same procedure is followed as in Example 21c) to prepare compound No. 22 from (cyclo N, N'-benzylphosphityl) (N, N'-dibenzylphosphinyl) α, α'-o-xylenediamine; compound No. 22 is thus obtained with a yield of 98%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt / hexane: 80/20).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 29-7, 08 (m, 29H, aromatic protons); 5.04 (d, ³ J _HP = 7.5 Hz, 2H, Ha '); 4, 99-4, 83 (m, 8H, Ha); 4, 81-4, 52 (m, 4H, Ha ").

¹³ C NMR: (CDCI ₃ ) 50MHz

 δ (ppm): 135, 84-135, 67 (4Cb, 1Cb ') 135, 05 (2Cb "); 128,92-127, 83 (8Cd, 8Cc, 2Ce, 2Cd', 2Cc ', 1Ce', 2Cd "and 2Cc"); 69, 16-68, 83 (4Ca and 1Ca '); 49.01 (2Ca ").

³¹ P NMR: (CDCI ₃ / HPO ₄ ) 81.015 MHz

δ (ppm): 8.11 (t, ² J = 18.9Hz, P ₂ and 4.09 (d, ² J = 18.9Hz, P1 and P3).

SM: (lC / CH ₄ )

m / z: 809 (MH ⁺ ).

IR (CH ₂ Cl ₂ ) cm ^-1 : Example 23 Preparation of (cyclo N, N'-methylphosphonyl) (N, N'-dibenzylphosphinyl) α, α'-o-xylenediamine (compound 23)

C ₃₇ H ₃₉ N ₂ O ₈ P ₃ PM: 732.64

 This compound is prepared by following the same procedure as in Example 22 from (cyclo N, N'-methylphosphityl) (N, N'-dibenzylphosphinyl) -o-xylene diamine using as methyldichlorophosphite as phosphorylating agent place of benzyldichlorophosphite. The phosphite formed is then oxidized according to the process which led to compound no. 21. Compound no. 23 is thus obtained with a yield of 40%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 35-6, 81 (m, 24H, aromatic protons); 5.03 (part AB syst.ABX, J _AB = 11.8Hz, J _AX = 7.9Hz, J _BX = 7.7Hz, νA = 5.08, vB = 4.99, 4H, Ha); 4.86 (m, 4H, Ha); 4, 77-4, 47 (td, ³ J _HP = 31Hz and J = 16.3Hz, 4H, Ha '); 3.69 (d, ³ J _HP = 11.7 Hz, 3H, Hf).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 135.90 and 135.69 (2d, ³ J _CP = 7.5Hz, ³ J _CP = 7.9Hz, 4Cb); 135.05 (2Cb '); 128.85-127, 79 (8Cc, 4Ce, 8Cd, 2Cc 'and 2Cd'); 69.11 and 68.88 (2d, ² J _CP = 5.7Hz and ² J _CP = 5.5Hz, 4Ca); 53.86 (d, ² J _CP = 5.5Hz, 1Cf); 48.91 (2Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz

δ (ppm): 9.25 (t, ² J = 18.9Hz, P ₂ ) and

4.14 (d, ² J = 18.9 Hz, P1 and P3).

SM: (lC / CH ₄ )

m / z: 733 (MH ⁺ ).

SM: (lC / NH ₃₎

m / z: 750.1 (MNH ₄ ⁺ ). 733.1 (MH ⁺ ).

 Example 24: Preparation of (N, N'-benzyl methyl phosphinyl) (cyclo N, N'-benzyl phosphinyl) α, α'-o-xylene diamine (compound No. 24).

a) Preparation of the

(N, N'-benzylmethylphosphinyl) α, α'-xylenediamine of formula:

The same procedure is followed as in Example 21a) to prepare this compound from α, α'-o-xylenediamine obtained in Example 22b) and benzyl methyl chlorophosphate prepared in Example

1b).

 There is thus obtained the (N, N'-benzyl methyl phosphinyl) g, g'-xylene diamine with a yield of

93%.

 The characteristics of this compound are as follows:

 CCM:

 Rf = 0.5 (AcOEt / EtOH: 85/15).

¹ H NMR: (CDCl ₃ ) 200 MHz

δ (ppm): 7.40-7.11 (m, 14H, aromatic protons); 4.96 (part AB system ABX, J _AB = 11.7 Hz,

J _AX = 7.7Hz, J _BX = 8.6Hz, ν _A = 5.01, v _B = 4.91, 8H, H _a );

4.14-4.04 (m, 4H, H _a ,); 3.64 (d, ² J _HP = 11.3 Hz, 3H, H _f );

3.56-3.50 (m, 2H, NH).

¹³ C NMR: (CDCl ₃ ) 50 MHz

δ (ppm): 137.25 and 136.45 (2d, ³ J _CP = 6.4Hz,

³ J _CP = 7.3, Hz, 2Cb 'and 2Cb); 129.13-127.74 (4Cd, 4Cc,

2Ce, 2Cd ', 2Cc'); 67.95 (d, ² J _CP = 4.9 Hz, 2Ca); 53.07 (d,

² J _CP = 5.5Hz, 2Cf); 42.42 (2Ca ').

³¹ P NMR: (CDCI ₃ .H ₃ PO ₄ ) 81.015 MHz δ (ppm): 10, 65 (s, 2P).

SM: (lC / NH ₃ )

m / z: 523.1 (MNH4 ⁺ ); 505.1 (MH ⁺ ).

IR (CH ₂ Cl ₂ ) cm ^-1 :

 3411; 3238; 3060; 3036; 2953; 2892; 2850;

1889; 1812; 1719; 1607; 1497; 1450; 1413; 1286; 1218; 1185; 1050; 911; 866 ;.

 b) Preparation of Compound No. 24

This compound is obtained in the same way as compound No. 23 from the

(N, N'-benzylemethylphoshinyl) α, α'-xylene diamine obtained previously using benzyl dichlorophosphite instead of methyl dichlorophosphite.

The phosphite formed is not isolated, but oxidized according to the process which led to compound no. 21. Compound no. 24 is thus obtained with a yield of 57%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt / EtOH: 97/3).

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

δ (ppm): 7, 50-7, 14 (m, 19H, aromatic protons); 5, 44-4, 46 (m, 10H, Ha, Ha 'and Ha "); 3, 68.3, 63,3,56 and 3,44 (4d, ³ J _HP = 11, 8Hz, 6H, Hf ).

¹³ C NMR: (CDCI ₃ ) 50 MHz, mixture of diastereoisomers:

δ (ppm): 135, 96-135, 13 (2Cb, 2Cb 'and 1Cb "); 129.01-127, 73 (4Cd, 4Cc, 2Ce, 2Cd', 2Cc ', 2Cd", 2Cc "and 1Ce"); 69, 15-68, 87 (m, ² J _CP = 5, 1Hz, 2Ca and 1Ca "); 54.10-53.74 (4d, ² J _CP = 5.3Hz, 2Cf); 48.95 (2Ca ³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz, mixture of diastereoisomers:

δ (ppm): 8, 36-6, 87 (4t, ² J _CP = 18, 7 Hz, P ₂₎ and from 5.47 to 5.14 (4d, ² J _PP = 18.7 Hz P ₁ and P ₃ ).

SM: (lC / NH ₃ )

m / z: 674.1 (MNH ₄ ⁺ ); 657.1 (MH ⁺ ). IR (CH ₂ Cl ₂ ) cm ^-1 :

 3069; 3033; 2957; 2853; 1956; 1889; 1812; 1719; 1498;

1455; 1378; 1310; 1215; 1005; 913; 811.

 Example 25: Preparation of (N-benzyl methyl phosphinyl) (cyclo N, N'-benzyl phosphinyl α, α'-o-xylene diamine) N'-benzyl hydrogenophosphate (compound No. 25).

298 mg (4.57 mmol, 1 eq.) Of potassium cyanide are added to a solution of 3 g (4.57 mmol, 1 eq.) Of compound No. 24 in 30 ml of anhydrous DMF. The mixture is stirred for 4 hours at 70 ° C. DMF is removed by vacuum distillation of a vane pump using a Hickmann condenser. The salt obtained is dissolved in 100 ml of a water / methanol mixture (30/70). An ion exchange resin loaded with H ₃ O ⁺ ions (Dowex 50X8) is added to the above solution and the mixture is stirred for 12 hours. The resin is recovered by filtration, the filtrate is concentrated and it is taken up 3 times with 100 ml of toluene. 2.76 g of compound 25 are thus obtained in the form of a yellow buile which can be used without any purification (94% yield).

 The characteristics of this compound are as follows:

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

 δ (ppm): 11.32 (broad s, 1H, POOH);

7, 44-7.05 (m, 19H, aromatic protons), 5, 37-4, 40 (m,

10H, Ha, Ha ', Ha "and Hf); 3, 63-3, 28 (m, 3H, Hk).

¹³ C NMR: (CDCI ₃ ) 50 MHz, mixture of diastereoisomers:

 δ (ppm): 135, 86-135, 68 (1Cb, 2Cb ', 1Cb "and

1Cg); 128.97-127.51 (2Cd, 2Cc, 1Ce, 2Cd ', 2Cc', 2Cd ",

2Cc ", 1Ce", 2Ch, 2Ci and 1Cj); 69, 02-68, 29 (1Ca, 1Ca "and 1Cf); 53.95 (1Ck); 48.83 (2Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz, mixture of diastereoisomers:

 δ (ppm): 8, 68-7, 76 (m, 1P); 5.34-5.04 (m, 1P);

4.43-2.41 (m, 1P).

Example 26: Preparation of (N-benzyl methyl phosphinyl) (N'-dibenzyl phosphinyl) (cyclo N, N'-benzyl phosphinyl) α, α'-o-xylene diamine (compound No. 26) ..

^

C ₃₇ H ₃₉ N ₂ O ₈ P ₃ PM: 732.64

 The procedure of Example 14 is followed from compound No. 12 to prepare compound No. 26 from compound No. 25 using benzyl alcohol instead of methyl alcohol. Compound No. 26 is thus obtained with a yield of 60%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

δ (ppm): 7.31-7.26 (m, 24H, aromatic protons); 5.08-4.86 (m, 12H, Ha, Ha ', Ha "and Hf); 3.60 and 3.48 (2d, ³ J _HP = 11.5 Hz, 3H, Hk).

¹³ C NMR: (CDCI ₃ ) 50 MHz, mixture of diastereoisomers:

 δ (ppm): 136.01-135.81 (2Cb, 1Cb "and 1Cg); 135.07 (2Cb '); 128, 99-127, 84 (4Cd, 4Cc, 2Ce, 2Cd', 2Cc ', 2Cd ", 2Cc", 1Ce ", 2Ch, 2Ci and lCj); 69, 21-68, 88 (2Ca, 1Ca "and 1Cf); 53.95 (1Ck); 48.95 (2Ca ').

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 81.015 MHz, mixture of diastereoisomers: δ (ppm): 8, 13-7, 18 (m, 1P); 5.38 and 5.28 (2d, ² J = 19Hz, 1P); 4.04 (d, ² J = 19Hz, 1P).

SM: (1C / NH ₃ )

m / z: 750.2 (MNH ₄ ⁺ ); 733.1 (MH ⁺ ).

IR (CH ₂ Cl ₂ ) cm ¹ :

 3046; 2996; 1889; 1812; 1736; 1593; 1550; 1421; 1266; 1030; 885; 768.

Example 27 Preparation of (N-dibenzyl phosphinyl) (cyclo N, N'-benzyl phosphinyl α, α'-o-xylene diamine) N'-benzyl hydrogenophosphate (compound no. 27)

C ₃₆ H ₃₇ N ₂ O ₈ P ₃ PM: 718.62

 The procedure of Example 25 is followed to prepare compound No. 27 from compound No. 26. The yield is 88%.

 The characteristics of this compound are as follows:

¹ H NMR: (CDCI ₃ ) 200MHz

 δ (ppm): 7.37-7.01 (m, 24H, aromatic protons); 5.12-4.82 (m, 8H, Ha, Ha "and Hf); 4.80-4.57 (m, 4H, Ha ').

¹³ C NMR: (CDCI ₃ ) 50MHz

 δ (ppm): 135, 83-134, 71 (2Cb, 1Cb ", 1Cg and 2Cb '); 129, 27-126, 98 (4Cd, 4Cc, 2Ce, 2Cd', 2Cc ', 2Cd", 2Cc ", 1Ce ", 2Ch, 2Ci and 1Cj); 69, 21-68, 22 (2Ca, 1Ca "and 1Cf); 48.09 (2Ca ').

SM: (1C / NH ₃ )

m / z: 735.5 (MNH ₄ ⁺ ); 418; 326; 218.

EXAMPLE 28 Preparation of 6-chloro-2 ', 3'-O-benzylidene-5' - [(N-dibenzylphosphinyl) (cyclo-N, N'-benzyl phosphinyl-α, α'-o-xylene-diamine) (N'-benzylphosphinyl)] - purine-9H (compound n ° 28)

C ₅₃ H ₅₀ CIN ₆ O ₁₁ P ₃ PM: 1075.38

The same procedure is followed as in Example 15 to prepare compound No. 28 from compound No. 27 and 6-chloro-2 ', 3'-O-benzylidene (5'-hydroxy) purine-9H . Compound No. 28 is thus obtained with a yield of 65%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

δ (ppm): 8, 69-8.44 (m, H ₈ and H ₂ ); 7.53-7.25 (m, 29H, aromatic protons); 6.31-6.26 (m, H ₁ ,); 5.92-5.86 (m, Hf); 5, 50-5, 31 (m, 1H, H ₂ ,); 5.29-5.14 (m, 1H, H ₃ ,); 5, 13-3, 81 (m, 15H, H in the benzylic position, H ₄ , and H5,).

 Example 29: Preparation of

6-azido-2 ', 3'-O-benzylidene-5' - [(N-dibenzyl

phosphinyl) (cyclo-N, N'-benzyl phosphinyl-α, α'-o-xylenediamine) (N'benzyl phosphinyl)] - purine-9H (compound no. 29).

C ₅₃ H ₅₀ N ₉ O ₁₁ P ₃ PM: 1081.95

The same procedure is followed as in Example 16 to prepare compound No. 29 from compound No. 27 and 6-azido-2 ', 3'-O-benzylidene

(5'-hydroxy) pyrin-9H. This gives compound n °

29 with a yield of 40%.

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (AcOEt).

¹ H NMR: (CDCl ₃ ) 200MH, mixture of diastereoisomers:

δ (ppm): 9.34 (m, 1H, H ₈ ); 8, 70-8, 46 (m, 1H, H ₂ );

7, 62-7, 23 (m, 29H, aromatic protons);

6.33-6.25 (m, H ₁ '); 5, 99-5, 83 (m, Hf); 5.60-5.30 (m, 1H, H ₂ ,); 5.29-5.11 (m, 1H, H ₃ ,); 5, 10-3, 82 (m, 15H, H in the benzylic position, H ₄ , and H ₅ ,).

IR (KBr) cm ^-1 :

 3057; 2985; 2896; 2147; 1738; 1638; 1505; 1422; 1223; 1108; 1074; 987.

 Example 30: Preparation of

(diethylphosphonodifluoromethyl) (dibenzylphosphonomethyl) (methyl phosphinate) (compound 30)

C ₂₁ H ₂₉ F ₂ O ₈ P ₃ PM: 540.37

a) preparation of diethyl difluoromethylphosphonate of formula:

At p 161:

C ₅ H ₁₁ F ₂ O ₃ P PM: 188.11

To a suspension of 2.28 g (57.18 mmol, 1.2 eq.) Of NaH (60% in oil) in 150 ml of anhydrous THF at -15 ° C, 6.14 is added dropwise ml (47.65 mmol, 1 eq.) of diethylhydrogenophosphite dissolved in 30 ml of anhydrous THF. The medium is stirred at room temperature for 1/2 hour and cooled to -50 ° C in order to bubble chlorodifluoromethane (Freon 21) there for 15 minutes. After one hour, freon is bubbled again for 15 minutes, then the solution is warmed to room temperature and stirred again for 12 hours. The excess hydride is hydrolyzed by addition of an aqueous solution saturated with NH ₄ Cl and the mixture is extracted twice with ethyl acetate. After drying and evaporation of the organic phases, the residue obtained is purified by chromatography on a silica column (ethyl ether / hexane: from 60/40 to 100/0); diethyldifluoromethyl phosphonate is thus obtained with a yield of 90%.

 The characteristics of this compound are as follows:

CCM:

Rf = 0.5 (Et ₂ O / hexane: 80/20).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 5.91 (td, J _HF = 49.5Hz, J _PH = 28.5Hz,

1H, H _c ); 4.31 (m, 4H, Ha); 1.38 (m, 6H, H _b) .

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 111.36 (td, J _CP = 211, 5Hz,

J _{C- F} = 256.2Hz, 1C _c); 64.12 (d, ² J _CP = 6.4 Hz, 2C _a); 16.01 (d, ³ J _CP = 5.3 Hz, 2C _b ).

 b) preparation of benzyl diethyl methyl difluoromethylenediphosphonate of formula:

C ₁₃ H ₂₀ F ₂ O ₆ P ₂ PM: 372.24

To 4.1 g (29.24 mmol, 1.1 eq.) Of diisopropylamine in 80 ml of anhydrous THF at -50 ° C., 18.27 ml of n-BuLi (1.6 mol / solution) are added dropwise. l in hexane, 1.1 eq.). The mixture is warmed to -20 ° C for 45 minutes, then to -78 ° C, 5 g (26.58 mmol, leq.) Of the diethyldifluoromethyl phosphonate obtained previously, dissolved in 50 ml of anhydrous THF, are added. After 15 minutes, a solution of 6.45 g (29.24 mmol, 1.1 eq.) Of the benzyl methyl chlorophosphate obtained in example 1b) is added in 50 ml of anhydrous THF. After 2 hours at -78 ° C., 200 ml of a saturated NH 4 Cl solution are added, the mixture is extracted with ethyl acetate, the organic phase is dried, the residue is evaporated in vacuo and the residue is chromatographed on a column silica (ethyl ether / hexane: from 70/30 to 100/0); 6.43 g of benzyl diethyl methyl difluoromethylene disphosphonate are thus obtained in the form of a yellow oil (yield of 65%).

 The characteristics of this compound are as follows:

CCM:

Rf = 0.45 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 7, 39-7, 35 (m, 5H, aromatic protons); 5.27 (part AB of an ABX, J _AB = 11.6Hz, J _AX = 7Hz, J _BX = 7.9Hz, ν _A , 5.32, v _b = 5.22, 2H, H _a ); 4.33 (m, 4H, H _f ); 3.89 (d, ³ J _HP = 10.3 Hz, 3H, H _h ); 1.37 (m, 6H,

H _g ).

¹³ C NMR: (CDCI ₃ ) 50MHz

δ (ppm): 135, 34 (d, ³ J _CP = 5.5 Hz, 1Cb);

128, 75-127, 87 (2Cd, 1Ce, 2Cc); 115.20 (tdd, J _CF = 271, 2

Hz, J _CP = 187.5Hz, J _CP = 185Hz, 1Ci); 70.25 (d,

2J _CP = 6.2Hz, 1Ca); 65.23 (dd,

2J _CP = 6.4Hz, ² J _CP = 9.6Hz, 2Cf); 55.08 (d, ² J _Cp = 6.3Hz, 1Ch); 16.24 (d, ² J _CP = 5.1Hz, 2Cg).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 121, 46MHz

 δ (ppm): 7, 10-2, 90 (m, 2P).

SM: (IC / NH ₃ )

m / z: 390.2 (MNH ₄ +); 373.2 (MH ⁺ ).

c) preparation of the acid (diethylphosphinyl)

(methyl) difluoromethylene phosphonic of formula:

C ₆ H ₁₄ F ₂ O ₆ P ₂ PM: 282.11

 Is subjected to a catalytic hydrogenolysis 2 g (5.37 mmol, 1 eq.) Of benzyl diethyl methyl difluoromethylene diphosphonate obtained previously in solution in 25 ml of ethyl acetate, in the presence of 200 mg (10% by mass) of Pd -C (10%) under an atmosphere of hydrogen at room temperature for 2 hours. The reaction medium is filtered on celite, the filtrate is evaporated to dryness and 1.48 g of the acid are thus obtained in the form of a colorless oil (yield 98%).

 The characteristics of this compound are as follows:

¹ H NMR: (CDCl ₃ ) 200 MHz

δ (ppm): 8.01 (s, broad 1H, POOH); 4.37 (m, 4H, Ha); 3.87 (d, ³ J _HP = 10.5 Hz, 3H, Hc), 1.35 (m, 6H, Hb). ¹³ C NMR: (CDCl ₃ ) 50Mhz

δ (ppm): 114.89 (tdd, J _CF = 271, 1Hz, J _CP = 187.1Hz, J _{C-P '} = 185Hz, lCd); 65.72 (d, ² J _CP = 6.4Hz, 2Ca); 54.99 (d, ² J _CP = 6Hz, 1Ce); 16, 16 (d, ² J _CP = 5, 4Hz, 2Cb).

SM: (IC / NH ₃ )

m / z: 300.2 (MNH ₄ ⁺ ).

IR (pure, film) cm ^-1 :

 3600/2350; 1694; 1446; 1394; 1250; 1164; 1053; 798.

d) preparation of (diethyl phosphinyl) difluoromethylene (methyl) chloroyhosphonate of formula:

C ₆ H ₁₃ ClF ₂ O ₅ P ₂ PM: 360.56

 To a solution of 2 g (7.09 mmol, 1 eq.) Of the (diethyl phosphinyl) (methyl) difluoromethyleneene phosphonic acid obtained above, in

50 ml of anhydrous benzene, added dropwise

1.85 ml (21.27 mmol, 3 eq.) Of oxalyl chloride and one drop of anhydrous DMF. The mixture is stirred for 2 hours at room temperature. The solution is reduced in vacuo and taken up 3 times with 20 ml of anhydrous toluene; 2.55 g of a colorless oil are thus obtained which can be used without any purification

(100% yield).

 The characteristics of this compound are as follows:

¹ H NMR: (CDCI ₃ ) 200MHz

δ (ppm): 4.38 (m, 4H, Ha); 4.09 (d, ³ J _HP = 12.8Hz, 3H, Hd); 1.41 (m, 6H, Hb).

 d) preparation of compound No. 30.

 To a solution of 3.92 g (14.18 mmol, 2 eq.) Of dibenzyl methyl phosphonate obtained in Example 1a), in 50 ml of anhydrous THF, cooled to -78 ° C., 8 is added dropwise, 86 mml of n-BuLi (solution

1.6 mol / in hexane, 2 eq.). The mixture is stirred for 1/4 hour at -78 ° C and a yellow color appears. At -78 ° C, 2.55 g are quickly added

(7.09 mmol, 1 eq.) (Diethyl phosphinyl) dichloromethylene (methyl) chlorophosphonate in solution in 20 ml of anhydrous THF. After 1/2 hour at -78 ° C, the reaction mixture is neutralized by addition of an aqueous solution saturated with NH ₄ Cl, then the organic phase is extracted twice with ethyl acetate. After drying and vacuum evaporation of the organic phases, the residue is chromatographed on a silica column (ethyl acetate / hexane / ethanol: from 70/30/0 to 95/0/5). 1.64 g of compound 30 are thus obtained in the form of a colorless oil (yield of 43%).

 The characteristics of this compound are as follows:

CCM:

 Rf = 0.5 (ACOEt / hexane: 85/15).

¹ H NMR: (CDCI ₃ ) 200MHz

 δ (ppm): 7.41-7.29 (m, 10H, aromatic protons); 5.11 (m, 4H, Ha); 4.37 (m, 4H, Hb);

3.89 (d, ³ J _Hp = 10.3 Hz, 3H, Hd); 2, 81 (ddd, J _AB = 30Hz,

J _HP = 20Hz, J _HP = 17.5Hz, 2H, He); 1.39 (m, 6H, Hc).

³¹ P NMR: (CDCI ₃ H ₃ PO ₄ ) 145.8 MHz

δ (ppm): 30.07 (tdd, JP _β-Pγ = 19, 2Hz, J _{Pβ -F} = 78.2Hz, ² J _Pβ-Pα = 60.9Hz, 1P, Pβ); 19.01 (d, J _P-γ-Pβ

= 19.2Hz, 1P, Pγ); 3.68 (td, ² J _Pα-Pβ = 60, 9Hz, J _Pα-F = 83, 7Hz, 1P, P _α ).

SM: (IC / NH ₃ )

m / z: 558.1 (MNH ₄ ⁺ ); 541 (MH ⁺ ).

Example 31 Preparation of (benzyl methyl phosphonomethyl) (diethyl phosphono-difluoromethyl) methyl phosphinate (compound no. 31)

C ₁₅ H ₂₅ F ₂ O ₈ P ₃ PM: 464.27 The same procedure is followed as in Example 30 to prepare this compound using the lithiated anion of benzyl methyl methylphosphonate instead of the lithiated anion of dibenzyl methylphosphonate. Compound No. 31 is thus obtained with a yield of

30 %.

 The characteristics of this compound are as follows:

 CCM:

 Rf = 0.5 (AcOEt / EtOH: 95/5).

¹ H NMR: (CDCI ₃ ) 200 MHz, mixture of diastereoisomers:

δ (ppm): 7, 41-7, 34 (m, 5H, aromatic protons); 5.21 and 5.15 (2d, 2H, Ha); 4.36 (m, 4H, Hb); 3.99 and 3.95 (2d, ³ J _HP = 10, 1Hz, 3H, Hd); 3.78 and

3.75 (2d, ³ J _HP = 11.6 Hz, 3H, He); 2.81 (m, 2H, Hf);

1.39 (m, 6H, Hc).

³¹ P NMR: (CDCI ₃ / H ₃ PO ₄ ) 145.8 MHz, mixture of diastereoisomers:

δ (ppm): 30.93 (tdd, ² J _Pβ-Pγ = 21Hz, J _Pβ

_-F = 82.1Hz, ² J _Pβ-Pα = 61Hz, 1P, Pβ); 20.10 and 19.95 (2d, J _Pγ

_-Pβ = 21Hz, 1P, Pγ); _3.69 (td, ² J _Pα-Pβ = 61Hz, J _Pα-F = 83, 1Hz, 1P, Pα).

SM: (IC / NH ₃ )

m / z: 481.8 (MNH ₄ ⁺ ); 464.8 (MH ⁺ ).

Example 32: Preparation of the compound of the following formula (compound 32):

5 ml of anhydrous toluene containing 1.0 g (1.59 mmol, 1.0 eq.) Of compound 10 and 178 mg (1.59 mmol, 1.0 eq.) Of quinuclidine are brought to reflux for 1 hour. . The solvent is evaporated off and the benzyl quinuclidinium salt obtained is used as it is for the following transformation.

To 110 mg (149 μmol, 1.0 eq.) Of the preceding salt in 2 ml of anhydrous toluene, 40 μl (447 μmol, 3.0 eq.) Of oxalyl chloride and a catalytic amount of DMF. After 1 hour, the medium is reduced under vacuum to 1 ml, then taken up with 5 ml of toluene and reduced again to 1 ml under vacuum. The operation is repeated 2 times. To the residue taken up in 2 ml of toluene, then the sodium alcoholate of the solketal (racemic isopropylidene glycerol) prepared from 25 μl (196 μmol, 1.3 eq.) Of solketal and 15 mg (372 μmol, 2 , 5 eq.) Of NaH in 2 ml of anhydrous toluene. After 6 hours at room temperature, the solvent is evaporated, the residue is taken up in methylene chloride and the organic phase is washed with an aqueous solution saturated with NH ₄ Cl, dried, reduced under vacuum and the residue is chromatographed (Et ₂ O) to give 104 mg of an oil (yield: 84%). The characteristics of this product are as follows (mixture of diastereomers):

CCM:

Rf = 0.4 (Et ₂ O).

¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.42-7.29 (m, 20H); 5.04-4.84 (m, 6H); 4.60 (t, J = 13.9.1 H); 4.25-3.57 (m, 6H); 1.44 (s, 3H); 1.29 (s, 3H). SM: (lC / NH ₃ )

m / z: 672 (MH ⁺ ); 679 (MNH ₄ ⁺ ).

Example 33: Preparation of the compound of the following formula (compound 33):

A mixture containing 80 mg (119 μmol, 1.0 eq.) Of compound 32, 180 mg (5.9 mmol, 25 eq.) Of ammonium formate, 20 mg of Pd / C at 10%, 4 ml of methanol and 1 ml of water is heated for 2 hours at 80 ° C. It is then filtered and evaporated to dryness. The residue is taken up in 5 ml of water and lyophilized to give 34 mg of very hygroscopic white powder (yield: 98%).

 The characteristics of this product are as follows:

¹ H NMR: (CD ₃ OD) 200 MHz

δ (ppm): 4.37-4.25 (m, 1H); 4.19-4.07 (m, 2H); 4.03-3.82 (m, 2H); 1.40 (s, 3H); 1.34 (s, 3H). Example 34: Preparation of the compound of the following formula (compound 34):

To a mixture of 74 mg (143 μmol, 1.0 eq.) Of 2 ', 3'-O-benzylidene-N ³ -benzyl-N ² - (N, N- dimethylformamidine) guanosine, 77 mg (143 μmol, 1.0 eq.) Of compound 10 and 160 mg (715 μmol, 5.0 eq.) Of triphenyl phosphine in 3 ml of anhydrous THF, 120 μl (715 μmol, 5.0 eq.) Of DEAD are added dropwise. drop. The solvent is evaporated off and the residue is chromatographed (AcOEt / benzene / EtOH: 50: 50: 0 to 80:20:20) to give 87 mg of amorphous solid (yield: 59%).

 The characteristics of this product are as follows (mixture of diastereomers):

CCM:

Rf = 0.3 (CH ₂ Cl ₂ / EtOH: 95: 5).

¹ H NMR: (CDCI ₃ ) 200 MHz

 δ (ppm): 8.45-8.43 (m, 1H); 7.74-7.64 (m, 1H); 7.49-7.19 (m, 30H); 6.12-6.09 (m, 1H); 6.05-6.01 and 5.91-5.88 (2m, 1H); 5.53 (m, 2H); 5.22-4.79 (m, 8H); 4.57 (td, J = 14.0, J = 5.8, 2H); 4.41-4.02 (m, 3H); 3.05 - 3.03 (m, 6H).

SM: (lC / NH ₃ )

m / z: 1036 (MH ⁺ ). Example 35: Preparation of guanosine-5 '- (α, β- imidodiphosphate) of the following formula (compound 35):

A mixture containing 62 mg (60 μmol, 1.0 eq.) Of compound 34, 300 mg (4.75 mmol, 80 eq.) Of ammonium formate, 30 mg Pd (OH) ₂ / C (20%) , 4 ml of methanol and 1 ml of water is heated at 80 ° C for 3 hours, in a sealed tube. The mixture is then filtered then evaporated and lyophilized with 5 ml of water and 10 μl of triethylamine. 36 mg of compound 35 are obtained in the form of a triethylammonium double salt (yield: 94%).

 The characteristics of this product are as follows:

¹ H NMR: (D ₂ O) 200 MHz

 δ (ppm): 8.22 and 8.02 (s, 1H); 5.75 (m, 1H); 4.57 (m, 1H); 4.34 (m, 1H); 4.15 (m, 1H); 3.97 (m, 2H); 2.99 (q, J = 7.0, 12H); 1.07 (t, J = 7.0, 18H).

Example 36: Preparation of the compound of the following formula (compound 36):

This compound is obtained in the same way as compound 34, from 2 ′, 3′-O-benzylidene-N ³ - benzyl-N ² - (N, N-dimethylformamidine) guanosine and from compound 2 (yield : 67%).

 The characteristics of this product are as follows (mixture of diastereomers):

 CCM:

Rf = 0.5 (CH ₂ Cl ₂ / EtOH: 95: 5).

¹ H NMR: (CDCI ₃ ) 200 MHz

 δ (ppm): 8.48 (m, 1H); 7.78-7.18 (m, 26H);

6.20 and 6.08 (d, J = 3.1, 1H); 6.13 and 5.98 (s, 1H); 5.51

(s, 2H); 5.40-4.99 (m, 8H); 4.50-4.21 (m, 3H); 3.09 (s,

3H); 3.05 (s, 3H); 2.59-2.38 (m, 2H).

SM: (lC / NH ₃ )

m / z: 946 (MH ⁺ ); 963 (MNH ₄ ⁺ ).

Example 37: Preparation of guanosine-5'-α, β- methylene diphosphate of the following formula (compound 37):

Compound 37 is obtained from 36 in the same way as 35 from 34 (yield: 63%).

 The characteristics of this product are as follows:

¹ H NMR: (D ₂ O) 200 MHz

 δ (ppm): 8.07 (m, 1H); 5.67 (d, J = 6.2, 1H); 4.40 (m, 1H); 4.34 (m, 1H); 4.11 (m, 1H); 3.96 (m, 2H);

2 29-2 01 (m 2H) Example 38: Preparation of the 5 '- (α, β-β, γ-bis-imido) adenosine triphosphate (compound 38) of formula:

A mixture containing 91 mg (84 μmol, 1.0 eq.) Of compound 29, 55 mg of Pd (OH) ₂ / C at 20%, 3 ml of t-BuOH and 3 ml of water is stirred under pressure d hydrogen (80 psi) for 12 hours. The catalyst is removed by filtration and the residue is reduced under vacuum and then lyophilized in 10 ml of water to yield

40 mg of a very hygroscopic white powder

(yield: 94%).

 The characteristics of this product are as follows:

¹ H NMR: (CDCI ₃ ) 200 MHz

 δ (ppm): 8.33 (s, 1H); 8.07 (s, 1H); 5.95 (d, J = 5.4, 1H); 4.60-4.51 (m, 2H); 4.24-4.18 (m, 1H); 4.07-3.92 (m, 2H).

Example 39 Preparation of Compound 2

 In this example, compound 2 is prepared from compound 9 as follows:

To 3.16 g (5.9 mmol, 1.0 2a.) Of compound 9 in 25 ml of anhydrous toluene, 0.66 g (5.9 mmmol, 1.0 eq.) Of Dabco is added and the mixture is heated all at reflux for 2 hours. The solvent is evaporated and the residue is taken up in 50 ml of ethyl acetate and washed with 5% Hcl. The organic phase is dried over Na ₂ SO ₄ , then reduced under vacuum to give 2.63 g of a slightly yellow oil (yield: 98%).

 Example 40: Preparation of tribenzyl methyl methylene bis phosphonate (compound No. 1). ,

a) Preparation of dibenzyl chloromethylene phosphonate of formula:

10.3 ml (73.9 mmol, 3.0 eq.) Of anhydrous triethylamine are added dropwise to 4.1 g (24.5 mmol, 1.0 eq.) Of chloromethylene phosphonic acid dichloride in 300 ml of anhydrous THF at 0 ° C. Then 5.6 ml (53.9 mmol, 2.2 eq.) Of benzyl alcohol dissolved in 50 ml of anhydrous THF are added slowly. The medium is stirred for 1 h at 0 ° C. and then 4 hours at room temperature. The precipitate formed is filtered and the filtrate is evaporated in vacuo. The residue is chromatographed (Et ₂ O / hexane: 1: 1 to 1: 0) to give 6.3 g of a colorless oil (yield: 83%).

 The characteristics of this product are as follows:

CCM:

Rf = 0.3 (Et ₂ O / hexane: 1: 1). ¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.37-7.35 (m, 10 H); 5.07 (part AB of an ABX system, J _AB = 13.8, J _AX = 8.8, J _BX = 7.8, ν _A = 5, 16, ν _B = 5, 06, 4 H ); 3.49 (d, J = 10.5.3 H).

¹³ C NMR: (CDCI ₃ ) 50 MHz

 δ (ppm): 135.80; 128.02; 127.89; 68.76 (d, J = 6.8); 31.19 (d, J = 91.7).

SM (CI / NH ₃ ):

m / z: 328.4 (MNH ₄ ⁺ ). b) Preparation of dibenzyl methyl phosphite of formula:

_{15 17 3}

To a solution of 25 ml (286.5 mmol, 1 eq.) Of phosphorus trichloride in 1.5 l of anhydrous ether, cooled to -78 ° C., 123.8 ml are added dropwise over 10 minutes ( 888.2 mmol, 3.1 eq.) Of anhydrous triethylamine. The reaction medium is then treated dropwise with 6.97 g (573.0 mmol, 2 eq.) Of benzyl alcohol dissolved in 300 ml of ether. After 5 hours, a solution of 11.62 ml (286.53 mmol, 1 eq.) Of anhydrous methanol diluted in 200 ml of anhydrous ether is added dropwise at -78 ° C. The solution is warmed to room temperature and stirred under argon for 4 hours. The precipitate formed is filtered, the solvent is evaporated under vacuum, the residue obtained is chromatographed on a silica column (Et ₂ O / hexane / Et3N: 50/50/1) to give 47.5 g of a colorless oil (yield: 60%).

The characteristics of this product are as follows:

CCM:

Rf = 0.5 (Et ₂ O / hexane / Et ₃ N: 60/40/1).

¹ H NMR: (CDCI ₃ ) 200 MHz

δ (ppm): 7.38-7.36 (m, 10H, aromatic protons); 5.01 (d, ³ J _HP = 7.7 HZ, 4H, H _a ); 3.65 (d, ³ J _H -P = 11 Hz, 3H, H _f ).

¹³ C NMR: (CDCI ₃ ) 50 MHz

δ (ppm): 137.93 (d, ³ J _CP = 6.16 HZ, 2C _b ); 128.10 (2C _d ); 126.95 (1C _e ); 126.86 (2C _C ); 63.62 (d, ² J _{C- P} = 11.1 Hz, 2C _a ); 48.76 (d, ² J _CP = 10.1 HZ, 1C _f ).

IR (pure, film) cm ^-1 :

 3080; 3067; 3031; 2940; 2876; 1604; 1497; 1454; 1375; 1211; 994.

SM (CI / NH ₃ ):

m / z: 277 (MH ⁺ ); 294 (MNH ₄ ⁺ ). c) Preparation of tribenzyl methyl methylene diphosphonate (compound No. 1).

 A mixture containing 8.73 g (31.6 mmol, 2.0 eq.) Of dibenzyl methyl phosphite and 4.91 g is stirred

(15.8 mmol, 1.0 eq.) Of dibenzyl chloromethylene phosphonate for 6 hours at 140 ° C under 6-10 torr. The crude reaction product is then directly chromatographed (AcOEt / hexane: 7: 3) to give 6.32 g of a colorless oil (yield: 87%).

The characteristics of this compound are identical to those of compound 1 of Example 1 Example 41: Preparation of tetrabenzylmethylene diphosphonate (compound No. 9).

 8.0 g (22.7 mmol, 2.0 eq.) Of tribenzyl phosphite and 3.5 g (11.3 mmol, 1.0 eq.) Of dibenzyl chloromethyl phosphonate are stirred for 8 hours at

140 ° C at 6-10 torr. The crude reaction product is then directly chromatographed (AcOEt / hexane: 8: 2 to 10: 0) to give 5.6 g of a colorless oil (yield:

92t%).

The characteristics of this compound are identical to those of the compound obtained in Example 2.

Claims

1. Non-hydrolyzable stable analog of diphosphate or triphosphate of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ which may be the same or different, represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylene bonds, an aralkyl group , an aryl group, a benzyl group unsubstituted or substituted by an alkyl group, a group derived from nucleoside or a group derived from a biomolecule;

- R ⁵ represents a hydrogen atom, an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valency state of metal M, a derivative group, of a nucleoside or a group derived from a biomolecule; - X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- X ³ represents O, S, or NH; - n is equal to 0 or 1; and

- when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from the groups alkyl and / or aryl, or include an optionally substituted phenyl ring,

provided that at least one of R ¹ and R ⁵ is a benzyl group and that X ¹ does not represent CH ₂ , CHF, CF ₂ , CCl ₂ or CHCL when n = 0 and R ⁵ represents something other than group derived from nucleoside or biomolecule.

2. Analog according to claim 1, characterized in that n is equal to 1.

3. Analog according to claim 2, characterized in that X ³ represents O and R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the benzyl group.

4. Analog according to claim 2, characterized in that X ³ represents O and R ⁵ represents a nucleoside derivative.

5. Analog according to any one of claims 2 to 4, characterized in that X ¹ and X ² represent CH ₂ .

6. Analog according to claim 2, characterized in that X ¹ and X ² represent CH ₂ , X ³ represents O, R ¹ , R ² , R ³ and R ⁴ represent the benzyl group, and R ⁵ represents a quaternary ammonium group , a hydrogen atom, the methyl group or a group derived from a nucleoside.

7. Analog according to claim 4 or 6, characterized in that R ⁵ represents adenosine.

8. Analog according to claim 2, characterized in that X ¹ and X ² represent CH ₂ , X ³ represents 0, R ¹ , R ² , R ⁴ and R ⁵ represent the benzyl group and R ³ represents the group α (tert - butyl) benzyl.

9. Analog according to claim 2, characterized in that X ¹ and X ² represent NR ⁶ and X ³ represents O.

10. Analog according to claim 9, characterized in that R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the benzyl group, and the two R ⁶ together form a hydrocarbon chain of formula - (CH ₂ ) ₂ - or

11. Analog according to claim 9, characterized in that the two R6 form together

, R ¹ 'R ² , R ⁴ and R ⁵ represent the benzyl group, and R ³ is the methyl group.

12. Analog according to claim 9, characterized in that the two R ⁶ form together

, R ¹ and R ⁵ are methyl groups and R ² , R ³ and R ⁴ are benzyl groups.

13. Analog according to claim 9, characterized in that the two R ⁶ form together

R ¹ , R ² , R ³ and R ⁴ are benzyl groups and R ⁵ is a hydrogen atom, the methyl group or 6-chloro- or 6-azido-2,3'-o-benzylidene adenosine.

14. Analogue according to claim 2, characterized in that X ¹ is CF ₂ , X ² is CH ₂ , R ¹ and R ² are ethyl groups, R ³ is methyl group, R ⁴ is benzyl group, and R5 is the methyl group or the benzyl group.

15. Analog according to claim 1, characterized in that n is equal to 0.

16. Analogue according to claim 15, characterized in that X ¹ is NH or N-benzyl, X ³ represents O, R ¹ , R ² and R ⁴ are allyl or benzyl groups, and R ⁵ is the benzyl group.

17. Analog according to claim 15, characterized in that X ¹ is N-benzyl, X ³ represents NH, R ¹ , R ² , R ⁴ and R ⁵ are benzyl groups.

18. Non-hydrolyzable stable analog of triphosphate of formula:

in which

- R ¹ , R ² , R ³ and R ⁴ which may be identical or different, represent a hydrogen atom, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal, an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group having one or more ethylenic bonds, an aralkyl group, an aryl group or a benzyl group unsubstituted or substituted by a alkyl group, a group derived from nucleoside or a group derived from a biomolecule;

- R ⁵ represents a hydrogen atom, an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a quaternary ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valency state of metal M, a derivative group, of a nucleoside or a group derived from a biomolecule; - X ¹ and X ² which may be identical or different, represent NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- X ³ represents O, S, or NH; and

- n is equal to 1; provided that at least one of R ¹ , R ² , R ³ and R ⁴ is a hydrogen atom, an ammonium group, a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal, and that at least one of R ¹ , R ² , R ³ and R ⁴ is different from a hydrogen atom, a quaternary ammonium group, and a metal of formula M _{1 / v} in which M represents the metal and v is the valence state of the metal.

19. Process for the preparation of a diphosphate or triphosphate analog of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ which may be the same or different, represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylene bonds, an aralkyl group , an aryl group, a group derived from nucleoside or a group derived from a biomolecule; - R ⁵ represents an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group except the benzyl group or benzyl substituted by an alkyl group, an aryl group, a group derived from a nucleoside or a group derived from a biomolecule; - X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- n is equal to 0 or 1; and

- when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from the groups alkyls, and / or aryl, or include an optionally substituted phenyl ring,

characterized in that it comprises the following stages: a) preparing a compound of formula:

in which R ' ¹ , R' ² , R ' ³ and R' ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylene bonds, an aralkyl group or an aryl group, X ¹ 'X ² and n are as defined above, and Bn is a benzyl or benzyl group substituted by an alkyl group, R' ² and R ' ⁴ being identical when R' ¹ is a benzyl group or benzyl substituted with an alkyl group,

b) subjecting the compound obtained in a) to a monoprotection to replace the group Bn by H, M _{1 / v} with M being a metal and v being the valence of this metal, or a quaternary ammonium group,

c) reacting the compound obtained in b) with an alcohol of formula R ⁵ OH in which R ⁵ has the meaning given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

 20. Process for the preparation of a diphosphate or triphosphate analog of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a group derived from nucleoside or group derived from a biomolecule; - R ⁵ represents an alkyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group except the benzyl group or benzyl substituted by an alkyl group, an aryl group, or a group derived from a nucleoside or a group derived from d 'a biomolecule; - X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- X ³ represents S or NH,

- n is equal to 0 or 1; and - when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from alkyl, and / or aryl groups, or include an optionally substituted phenyl ring,

characterized in that it comprises the following stages: a) preparing a compound of formula:

in which R ' ¹ , R' ² , R ' ³ and R' ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group having one or more ethylenic bonds, a group aralkyl or an aryl group, X ¹ , X ² and n are as defined above, and Bn is a benzyl or benzyl group substituted by an alkyl group, R ' ² and R' ⁴ being identical when R ' ¹ is a benzyl group or benzyl substituted with an alkyl group, b) subjecting the compound obtained in a) to a monodeprotection to replace the group Bn with H, M _{1 / v} with M being a metal and v being the valence of this metal, or a quaternary ammonium group,

c) reacting the compound obtained in b) with a compound of formula R ⁵ X ³ H to replace OH by X ³ R ⁵ , X ³ and R ⁵ having the meanings given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

 21. Process for the preparation of a diphosphate or triphosphate analog of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a group derived from nucleoside or group derived from a biomolecule; - R ⁵ represents an alkyl group, except the methyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group or a group derived from a nucleoside or a group derived from a biomolecule; - X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group;

- n is equal to 0 or 1; and

- when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from the groups alkyl and / or aryl, or include an optionally substituted phenyl ring,

characterized in that it comprises the following stages: a) preparing a compound of formula:

in which :

- R ' ¹ , R' ² , R ' ³ and R' ⁴ , independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group or an aryl group, X ¹ 'X ² and n are as defined above, and Me is a methyl group, R' ² and R ' ⁴ being identical when R' ¹ is a methyl group,

b) subjecting the compound obtained in a) to a mono-protection to replace the group Me by H, M _{1 / v} with M representing a metal and v being the valence of this metal, c) reacting the compound obtained in b) with an alcohol of formula R ⁵ OH in which R5 has the meaning given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

 22. Process for the preparation of a diphosphate or triphosphate analog of formula:

in which :

- R ¹ , R ² , R ³ and R ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group, a group derived from nucleoside or group derived from a biomolecule;

R ⁵ represents an alkyl group except the methyl group, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group, an aryl group or a group derived from a nucleoside or a group derived from a biomolecule;

- X ¹ and X ² which may be identical or different, represent CH ₂ , CHF, CF ₂ , CCl ₂ , CHCl or NR ⁶ with R ⁶ representing a hydrogen atom, or an alkyl, aryl or aralkyl group; - X ³ represents S or NH;

- n is equal to 0 or 1; and

- when n is equal to 1 with X ¹ and X ² both representing NR ⁶ , the two R ⁶ may together form a hydrocarbon chain R9 of 2 to 7 carbon atoms, which may contain one or more substituents chosen from the groups alkyl and / or aryl, or include an optionally substituted phenyl ring,

characterized in that it comprises the following stages: a) preparing a compound of formula:

in which :

- R ' ¹ , R' ² , R ' ³ and R' ⁴ independently represent an alkyl group, an alkyl group substituted by one or more halogen atoms, a hydrocarbon group comprising one or more ethylenic bonds, an aralkyl group or a aryl group, X ¹ , X ² and n are as defined above, and Me is a methyl group, R ' ² and R' ⁴ being identical when R ' ¹ is a methyl group,

b) subjecting the compound obtained in a) to a monodeprotection to replace the group Me by H, M _{1 / v} with M being a metal and v being the valence of this metal, or a quaternary ammonium group, and

c) reacting the compound obtained in b) with a compound of formula R ⁵ X ³ H to replace OH with X ³ R ⁵ , X ³ and R ⁵ having the meanings given above, and

d) when R ¹ , R ² , R ³ and / or R ⁴ must be different from R ' ¹ , R' ² , R ' ³ and R' ⁴ , repeat the reactions of steps b) and c) to replace R ' ¹ , R' ² , R ' ³ and / or R' ⁴ by the R ¹ , R ² , R ³ and / or R ⁴ desired.

23. Method according to any one of claims 19 and 20, characterized in that n being equal to 1, X ¹ and X ² representing CH ² , R ¹ being a benzyl group, and R ² and R ⁴ being identical, prepares the compound of formula:

by reaction of a bis- (halomethylene) phosphinate of formula: X

in which R ³ is as defined in claim 1 and X is a halogen atom, with two equivalents of a benzyl phosphite of formula:

wherein Bn is benzyl or substituted benzyl and R ' ² is as defined in claim 19.

24. Method according to any one of claims 21 and 22, characterized in that n being equal to 1 and X ¹ and X ² representing CH ₂ , the compound of formula is prepared:

by performing the following successive steps:

 a) reacting a bis- (halomethylene) phosphinate of formula:

wherein R ' ³ is as defined in claim 1 with an equivalent of a benzyl phosphite of the formula:

wherein R ' ¹ and R' ² are as defined in claims 20 and 21, and Bn is a benzyl group or substituted benzyl to obtain a compound of formula:

and

b) reacting the compound thus obtained with an equivalent of a benzyl phosphite of formula:

OB

wherein R'4 is as defined in claims 20 and 21, Bn is a benzyl or substituted benzyl group and Me is a methyl group.

25. The method of claim 19 or

20, characterized in that n being equal to 0 and X ¹ representing CH ₂ , the compound of formula is prepared:

by reaction of a halomethylenephosphonate of formula:

in which R ' ¹ and R' ² are as defined in claim 18 and X is a halogen atom with a benzyl phosphite of formula:

wherein Bn is benzyl or substituted benzyl and R ' ⁴ is as defined in claim 18.

26. The method of claim 21 or 22, characterized in that n being equal to 0 and X ¹ representing CH ₂ , the compound of formula is prepared:

by reaction of a halomethylenephosphonate of formula:

in which R ' ¹ and R' ² are as defined in claim 20 and X is a halogen atom, with a benzyl phosphite of formula:

wherein Bn is the benzyl or substituted benzyl group, Me is the methyl group and R ' ⁴ is as defined in claim 20.

27. Method according to any one of claims 19 and 20, characterized in that n being equal to 1, X ¹ and X ² representing NR ⁶ with the two R ⁶ forming a hydrocarbon chain R ⁹ as defined in claim 1 , the compound of formula is prepared:

by performing the following steps:

 a) reacting two chlorophosphates of formulas:

with a diamine of formula: H ₂ NR ⁹ -NH ₂ in which R ' ¹ , R' ² , and R ' ⁴ are as defined in claim 18, and R ⁹ has the meaning given above to form a bis-phophoramide,

 b) cyclizing the bis phosphoramide thus obtained on a dichlorophosphite of formula:

Cl ₂ P-OR ' ³ wherein R' ³ is as defined in claim 18, and

 c) oxidizing the cyclized product thus obtained.

28. Method according to any one of claims 21 and 22, characterized in that n being equal to 1, X ¹ and X ² representing NR ⁶ with the two R ⁶ forming a hydrocarbon chain R ⁹ as defined in claim 1 , the compound of formula is prepared:

by performing the following steps:

 a) reacting two chlorophosphates of formulas:

with a diamine of formula

H ₂ NR ⁹ -NH ₂ in which R ¹ , R ² , R ⁴ and R ⁵ are as defined in claim 18, and R ⁹ has the meaning given above to form a bis-phophoramide,

 b) cyclizing the bis phosphoramide thus obtained on a dichlorophosphite of formula:

Cl ₂ P-OR ' ³ wherein R' ³ is as defined in claim 18, and

 c) oxidizing the cyclized product thus obtained.

29. Method according to any one of claims 19 and 20, characterized in that n being equal to 0, X ¹ representing NH, and R ' ¹ , R' ² and R ' ⁴ representing Bn, the compound of formula is prepared :

in which R ' ¹ , R' ² and R ' ⁴ are as defined above by reacting the compound of formula:

with a compound of formula BnOH.

30. Method according to any one of claims 19 and 20, characterized in that n being equal to 1, X ¹ representing CH ₂ and X ² representing NR ⁶ , the compound of formula is prepared:

in which R ' ¹ , R' ² , R ' ³ , R' ⁴ , and R ⁶ have the meanings given in claim 18, by reacting a methyl phosphonate of formula:

with a diphosphate analog of the formula

not

in which R ' ¹ , R' ² , R ' ³ , R' ⁴ and R ⁶ are as defined above.

31. Method according to any one of claims 19 to 22, characterized in that R ⁵ being a nucleoside derivative, in step c) the compound obtained in step b) is reacted with a nucleoside of formula:

in which B is an optionally substituted pyrimidine or purine base, P ¹ and P ² are protective groups or hydrogen atoms and P ³ is a protective group, and the protective group (s) is then removed if necessary (s).

32. Process for the preparation of a diphosphate or triphosphate analog of formula:

in which R ² , R ³ and R ⁴ represent H, a metal of formula M _{1 / v} with M being the metal and v the valence of this metal, or a quaternary ammonium group, R ¹ is identical to R ² , R ³ and R ⁴ or is a group derived from nucleoside or a biomolecule, X ¹ , X ² and n have the meanings given in claim 1, and R ⁵ represents a group derived from nucleoside or a biomolecule, characterized in what is reacted with a compound of formula:

in which R ¹ represents H or has the meaning given in claim 1, R ² , R ³ , R ⁴ , X ¹ , X ² and n have the meanings given in claim 1 with a compound of formula R ' ⁵ OH in which R ' ⁵ is the group R ⁵ or a precursor thereof, and then the groups R ² , R ³ , R ⁴ and optionally R ¹ are eliminated to replace them with H, M _{1 / v} or a quaternary ammonium group .

33. Method according to claim 32, characterized in that R ⁵ is a group derived from nucleoside and in that the compound R ' ⁵ OH is a nucleoside of formula:

in which B is an optionally substituted pyrimidine or purine base, P ¹ and P ² are protective groups or hydrogen atoms and P ³ is a protective group, and in that the group (s) is then removed ( s) protector (s) P ¹ , P ² and / or P ^{3 as} well as the groups R ¹ , R ² , R ³ and R ⁴ .